Clitoral Epidermal Inclusion Cyst Leading to Anorgasmia: A Case Report and Literature Review.

BACKGROUND: Clitoral epidermal inclusions cysts are most frequently seen following trauma, especially female genital mutilation. Spontaneous clitoral epidermal inclusion cysts are rare with an unclear etiology and their impact on later sexual function has not been described. CASE: A 15-year-old spontaneously developed a clitoral mass that progressively enlarged over seven years, ultimately leading to secondary anorgasmia. Surgical removal resulted in restoration of normal anatomy and complete return of clitoral function. Final pathology revealed the mass to be an epidermal inclusion cyst. SUMMARY AND CONCLUSION: Clitoral epidermal inclusion cysts typically present in childhood or early adolescence and can lead to sexual dysfunction if left untreated. Physicians must consider the potential sequelae of these cysts when counseling and managing these patients.

How Are Patients With Prostate Cancer Managing Androgen Deprivation Therapy Side Effects?

BACKGROUND: Androgen deprivation therapy (ADT) for prostate cancer has numerous side effects. Clinical guidelines for side effect management exist; however, these are not always integrated into routine practice. What remains undocumented and therefore the objective of this study, is to describe patients' willingness to employ established strategies. PATIENTS AND METHODS: Study participants were 91 men who had attended an educational program (ie, attend a class plus read a book), designed to prepare patients for managing ADT side effects. Three months later, patients completed the ADT Management Strategies Inventory, to determine use of strategies. Descriptive analyses were conducted. RESULTS: At the time of class attendance, the average ADT duration was 133 days. Patient preferences for a variety of strategies for each side effect are presented. Highlights include: a high degree (> 65%) of patients using or willing to use exercise to manage medical risks and physical side effects. Forty percent of patients continued to engage in non-penetrative sexual activities, despite reduced sexual desire and erectile dysfunction. CONCLUSIONS: When educated about options, patients are willing to use a wide array of ADT management strategies. Consequently, health care providers should ensure that patients know about side effects and how to manage them. Exercise appears to be the single best strategy to encourage, because it is helpful in managing many side effects (eg, weight gain, muscle weakening, fatigue) and reducing medical risks of ADT (eg, cardiovascular disease, type II diabetes, and osteoporosis). A general trend was patient's preference for behavioral and lifestyle strategies over pharmacologic interventions.

Maintaining sexual function after pelvic floor surgery.

Sexual dysfunction in women with prolapse and incontinence is well documented in the literature, but the impact of treatment, particularly surgical correction, remains very limited and confusing. Age, on the other hand, has been shown to be an independent risk factor for deteriorating sexual function, with all aspects of the sexual function (i.e. desire, arousal, penetration, and orgasm) being affected. When combined with surgical correction of prolapse or incontinence there is potential for further worsening of sexual function, and hence this should be assessed before any pelvic floor surgery and patient expectations established. In this article the current evidence will be reviewed looking at the impact of pelvic floor dysfunction on sexual function and the effect of commonly performed surgery for these problems. Ways and means of preserving sexual function in women undergoing corrective surgery will also be investigated.

A Randomized Trial of a Relationship-Enhancement Approach in Improving Marital Intimacy in Middle-Aged Iranian Couples.

The purpose of this study was to evaluate the effects of a relationship enhancement education and counseling (REEC) program on improving middle-aged couples' marital intimacy. The randomized controlled trial study was conducted in Tabriz, Iran, from May to December 2017. Thirty-two married couples, attending a public health center and meeting the inclusion criteria, were randomly assigned to the intervention (receiving REEC) and control (receiving routine care) groups. The outcome measures were marital intimacy, sexual motivation, and sexual function. Data were collected at three points in time. The Statistical Package for the Social Sciences was used for the purpose of data analysis. In all analyses, the interventional group outperformed the control group on all outcome measures. In the intervention group, results showed statistically significant improvement in all variables of interest after one week and 12 weeks in comparison with preintervention. Upon the completion of the experimentation, it can be concluded that a REEC program positively affects marital intimacy, sexual function, and sexual motivation in middle-aged couples.

Online-based interventions for sexual health among individuals with cancer: a systematic review.

BACKGROUND: Online interventions have the advantages of being widely available, accessible, comfortable, cost effective, and they can provide tailored information and support. Despite these benefits, the effects of specifically devised online intervention programs for cancer patients' sexual problems are somewhat unclear. The aim of this review is to describe online-based interventions and to assess their effects on sexual health among cancer survivors and/or their partners. METHODS: We investigated the effects of online sexual interventions among individuals with cancer or their partners. Among these, we considered 4 eligible articles. RESULTS: Despite the diversity of contents of the interventions, the identified modes of delivery among most of the interventions were as follows: education, interactive methods, cognitive behavior therapy, tailored information, and self-monitoring. Methods of monitoring the interventions, including the utilization of the web site and post-treatment program rating, were reported. All the online intervention programs incorporated a focus on physical, psychological, cognitive, and social aspects of sexual health. Significant effects on patient sexual function and interest and the psychological aspect of sexual problems were reported. CONCLUSION: This study provides evidence that online-based interventions would be effective in improving the psycho-sexual problems of cancer survivors and their partners.

Importancia de una intervención psicoeducativa sobre sexualidad en mujeres sometidas a una histerectomía: una revisión de la literature / Importance of a psychoeducational intervention on sexuality in women undergoing a hysterectomy: a review of the literature

RESUMEN: La Histerectomía es uno de los procedimientos quirúrgicos ginecológicos más frecuentes en el tratamiento de patologías uterinas. La literatura destaca al útero como un símbolo de identidad femenina y aunque existen diferencias individuales de afrontamiento, su extirpación puede causar alteraciones en la dimensión psicológica, física, social y sexual. El objetivo del estudio es determinar la importancia de una intervención psicoeducativa en mujeres ginecológicas histerectomizadas, para prevenir el riesgo potencial de presentar alteraciones emocionales y disfunciones sexuales post cirugía. METODOLOGÍA: Se revisaron 106 artículos originales de fuente primaria, en inglés, español, francés y portugués, publicados entre los años 2004 y 2016, en PubMed, Scielo, CINAHL, Ciber Index Cuiden, Lilacs, Elsevier y Scopus. RESULTADOS: El 100% de artículos reconocen en mujeres histerectomizadas, el riesgo de sufrir alteraciones emocionales y trastornos sexuales y el 61% reconoce, además la importancia de entregar educación sexual formal a la mujer y pareja, para prevenir trastornos sexuales, especialmente en histerectomizadas oncológicas, considerando intervinientes individuales y multidimensionales, temáticas de interés y capacitación de profesionales sanitarios en educación sexual. CONCLUSIONES: Una intervención psicoeducativa en la mujer y pareja, puede prevenir especialmente en histerectomizadas oncológicas la aparición de alteraciones emocionales y disfunciones sexuales, propiciar la recuperación física y emocional, un retorno a una vida sexual activa satisfactoria. Se sugieren estudios que comprueben la magnitud de esta intervención, para ser incorporada en un futuro al protocolo de atención de Garantías Explicitas en Salud en mujeres con cáncer cérvico uterino.

ABSTRACT: Hysterectomy is one of the most frequent gynecological surgical procedures in the treatment of uterine pathologies. Literature stands out uterus as a symbol of female identity and although there are individual differences in confronting, their extirpation can cause alterations in the psychological, physical, social and sexual dimensions. The objective of the study is to determine the importance of a psychoeducational intervention in hysterectomized gynecological women in order to prevent the potential risk of presenting emotional alterations and sexual dysfunctions after surgery. METHODOLOGY: 106 original articles of primary source in English, Spanish, French and Portuguese, published between 2004 and 2016, in PubMed, Scielo, CINAHL, Ciber Index Cuiden, Lilacs, Elsevier and Scopus were reviewed. RESULTS: 100% of articles recognize in hysterectomized women, the risk of suffering emotional alterations and sexual disorders, and 61% also recognize the importance of providing formal sexual education to women and partners in order to prevent sexual disorders, especially in oncological hysterectomized, considering individual and multidimensional interveners, topics of interest and training of health professionals in sexual education. CONCLUSIONS: A psychoeducational intervention in the woman and couple can prevent, especially in oncological hysterectomized, the appearance of emotional alterations and sexual dysfunctions, to propitiate the physical and emotional recovery, a return to an active satisfactory sexual life. Studies to prove the magnitude of this intervention are suggested in order to be incorporated in future to the care protocol for Explicit Health Guarantees in women with cervical cancer.

Brain Activity Unique to Orgasm in Women: An fMRI Analysis.

BACKGROUND: Although the literature on imaging of regional brain activity during sexual arousal in women and men is extensive and largely consistent, that on orgasm is relatively limited and variable, owing in part to the methodologic challenges posed by variability in latency to orgasm in participants and head movement. AIM: To compare brain activity at orgasm (self- and partner-induced) with that at the onset of genital stimulation, immediately before the onset of orgasm, and immediately after the cessation of orgasm and to upgrade the methodology for obtaining and analyzing functional magnetic resonance imaging (fMRI) findings. METHODS: Using fMRI, we sampled equivalent time points across female participants' variable durations of stimulation and orgasm in response to self- and partner-induced clitoral stimulation. The first 20-second epoch of orgasm was contrasted with the 20-second epochs at the beginning of stimulation and immediately before and after orgasm. Separate analyses were conducted for whole-brain and brainstem regions of interest. For a finer-grained analysis of the peri-orgasm phase, we conducted a time-course analysis on regions of interest. Head movement was minimized to a mean less than 1.3 mm using a custom-fitted thermoplastic whole-head and neck brace stabilizer. OUTCOMES: Ten women experienced orgasm elicited by self- and partner-induced genital stimulation in a Siemens 3-T Trio fMRI scanner. RESULTS: Brain activity gradually increased leading up to orgasm, peaked at orgasm, and then decreased. We found no evidence of deactivation of brain regions leading up to or during orgasm. The activated brain regions included sensory, motor, reward, frontal cortical, and brainstem regions (eg, nucleus accumbens, insula, anterior cingulate cortex, orbitofrontal cortex, operculum, right angular gyrus, paracentral lobule, cerebellum, hippocampus, amygdala, hypothalamus, ventral tegmental area, and dorsal raphe). CLINICAL TRANSLATION: Insight gained from the present findings could provide guidance toward a rational basis for treatment of orgasmic disorders, including anorgasmia. STRENGTHS AND LIMITATIONS: This is evidently the first fMRI study of orgasm elicited by self- and partner-induced genital stimulation in women. Methodologic solutions to the technical issues posed by excessive head movement and variable latencies to orgasm were successfully applied in the present study, enabling identification of brain regions involved in orgasm. Limitations include the small sample (N = 10), which combined self- and partner-induced stimulation datasets for analysis and which qualify the generalization of our conclusions. CONCLUSION: Extensive cortical, subcortical, and brainstem regions reach peak levels of activity at orgasm. Wise NJ, Frangos E, Komisaruk BR. Brain Activity Unique to Orgasm in Women: An fMRI Analysis. J Sex Med 2017;14:1380-1391.

Obesity and Sexual Dysfunction: Making the Connection.

Understanding the relationship between the two may motivate patients to discuss weight loss.

What's new in the world of postmenopausal sex?

PURPOSE OF REVIEW: The purpose of this review is to describe new terminology for vulvovaginal atrophy and female sexual dysfunction and to highlight recent findings related to vaginal moisturizers, lubricants and prescription estrogen preparations. RECENT FINDINGS: Sexual health is a marker for overall health. A minority (40%) of healthcare providers routinely ask about sexual problems and its impact on quality of life. New terminology by the American Psychiatric Association divides female sexual disorders into three categories: arousal/interest disorder, orgasmic disorder and genital pain and penetration disorder. First-line therapy for genitourinary syndrome of menopause includes over-the-counter vaginal lubricants and moisturizers, followed by topical estrogen formulations. Progesterones are generally not needed when topical low-dose estrogen is prescribed. A systemic selective estrogen receptor modulator, designed specifically for genitourinary menopausal symptoms, is an option for patients who do not tolerate local estrogen. SUMMARY: Female sexual dysfunction is prevalent and causes distress, particularly among women at midlife. Although hypoactive sexual desire disorder may be the most prevalent dysfunction, dyspareunia and pain, particularly related to genitourinary and vulvovaginal atrophy, are also very common. Over-the-counter lubricants and prescription strength estrogen formulations are generally effective and well tolerated.

Couple-Based Psychosexual Support Following Prostate Cancer Surgery: Results of a Feasibility Pilot Randomized Control Trial.

INTRODUCTION: Surgery for prostate cancer can result in distressing side effects such as sexual difficulties, which are associated with lower levels of dyadic functioning. The study developed and tested an intervention to address sexual, relational, and emotional aspects of the relationship after prostate cancer by incorporating elements of family systems theory and sex therapy. AIMS: To develop and test the feasibility and acceptability of relational psychosexual treatment for couples with prostate cancer, determine whether a relational-psychosexual intervention is feasible and acceptable for couples affected by prostate cancer, and determine the parameters for a full-scale trial. METHODS: Forty-three couples were recruited for this pilot randomized controlled trial and received a six-session manual-based psychosexual intervention or usual care. Outcomes were measured before, after, and 6 months after the intervention. Acceptability and feasibility were established from recruitment and retention rates and adherence to the manual. MAIN OUTCOME MEASURES: The primary outcome measurement was the sexual bother subdomain of the Expanded Prostate Cancer Index Composite. The Hospital Anxiety and Depression Scale and the 15-item Systemic Clinical Outcome and Routine Evaluation (SCORE-15) were used to measure emotional and relational functioning, respectively. RESULTS: The intervention was feasible and acceptable. The trial achieved adequate recruitment (38%) and retention (74%) rates. The intervention had a clinically and statistically significant effect on sexual bother immediately after the intervention. Small decreases in anxiety and depression were observed for the intervention couples, although these were not statistically significant. Practitioners reported high levels of adherence to the manual. CONCLUSION: The clinically significant impact on sexual bother and positive feedback on the study's feasibility and acceptability indicate that the intervention should be tested in a multicenter trial. The SCORE-15 lacked specificity for this intervention, and future trials would benefit from a couple-focused measurement.

[Sex- and gender-aspects in regard to clinical practice recommendations for pre-diabetes and diabetes]. / Geschlechtsspezifische Aspekte für die klinische Praxis bei Prädiabetes und Diabetes mellitus.

Metabolic diseases dramatically affect life of men and women from infancy up to old age and are a major challenge for clinicians. Health professionals are confronted with different needs of women and men. This article aims at an increase of gender awareness and the implementation of current knowledge of gender medicine in daily clinical practice with regard to pre-diabetes and diabetes. Sex and gender affect screening and diagnosis of metabolic diseases as well as treatment strategies and outcome. Impaired glucose and lipid metabolism, regulation of energy balance and body fat distribution are related to steroid hormones and therefore impose their influence on cardiovascular health in both men and women. Furthermore, education, income and psychosocial factors relate to development of obesity and diabetes differently in men and women. Males appear to be at greater risk of diabetes at younger age and at lower BMI compared to women, but women feature a dramatic increase of their cardiometabolic risk after menopause. The estimated future years of life lost owing to diabetes is somewhat higher in women than men, with higher increase of vascular death in women, but higher increase of cancer death in men. In women pre-diabetes or diabetes are more distinctly associated with a higher number of vascular risk factors, such as inflammatory parameters, unfavourable changes of coagulation and blood pressure. Pre-diabetic and diabetic women are at much higher relative risk for vascular disease. Women are more often obese and less physically active, but may even have greater benefit from increased physical activity than males. Whereas men predominantly feature impaired fasting glucose, women often show impaired glucose tolerance. A history of gestational diabetes or the presence of a PCOS or increased androgen levels in women, on the other hand the presence of erectile dysfunction (ED) or decreased testosterone levels in men are sex specific risk factors for diabetes development. ED is a common feature of obese men with the Metabolic Syndrome and an important predictor of cardiovascular disease. Diabetic women also feature sexual dysfunctions much more frequently than non-diabetic women which should be addressed in clinical care. Several studies showed that diabetic women reach their targets of metabolic control (HbA1c), blood pressure and LDL-cholesterol less often than their male counterparts, although the reasons for worse treatment outcome in diabetic females are not clear. Furthermore, sex differences in action, pharmacokinetics, and side effects of pharmacological therapy have to be taken into account.

Discussing reproductive health in spinal care, part II: fertility issues.

PURPOSE: Due to advancing insights, discussing fertility in spinal care is an emerging topic. Studies among neurosurgeons to evaluate clinical practice about discussing fertility are non-existent. The aim of this study is to review knowledge, attitude and practice patterns regarding discussing fertility in spinal care. METHODS: Dutch neurosurgeons and residents were sent a mail-based questionnaire addressing attitude, knowledge and practice patterns regarding discussing fertility. RESULTS: Response rate was 62 % (compared to mean of 28 % in similar surveys) with 89 questionnaires suitable for analysis. Mean age was 42 years with 83 % of respondents being male. A quarter of respondents stated neurosurgeons are responsible to discuss fertility, with 12 % indicating to actually do this. Fertility is discussed more often with patients with cauda equina syndrome (70 %) and with men (p = 0.006). Merely 8 % of respondents stated to have adequate knowledge on fertility preservation (FP); this percentage was higher for doctors with spinal surgery as specialty (p = 0.015). In case of cauda equina syndrome, doctors with more knowledge discussed fertility more often (p = 0.002). Fifty-three percent of neurosurgeons wished to enhance their knowledge, in order to feel more comfortable to discuss fertility with their patients. Five percent indicated to have ever referred a patient to a fertility specialist. CONCLUSION: With the exception of cauda equina syndrome, fertility is not routinely discussed in spinal care. Fertility is discussed more often with men. Recent guidelines state that discussing fertility is an essential part of good practice in spinal care. Education on fertility and FP needs to be integrated in the neurosurgical training program to create more awareness, and to enable clinicians to provide adequate information and care to the patient.

Pilates for Better Sex: Changes in Sexual Functioning in Healthy Turkish Women After Pilates Exercise.

Although a large number of studies report the impact of daily exercise on many aspects of women's health, none of them address the relationship between Pilates exercise and sexual function prospectively. The aim of this study was to assess the effect of Pilates exercise on sexual function in healthy young women using a validated questionnaire. In total, 34 premenopausal healthy Turkish women aged between 20 and 50 years who had regular menstrual cycles and sexual relationships were included in the study. Women were asked to complete Beck Depression Inventory (BDI) and Female Sexual Function Index (FSFI) questionnaires. Questionnaires were completed before and after 12 weeks of Pilates exercise. Primary endpoints were changes in total and individual domain scores on the FSFI and BDI. After the 12-week Pilates intervention, BDI scores were decreased and all domains of the FSFI were significantly improved with mean ± SD total FSFI scores increasing from 25.9 ± 7.4 to 32.2 ± 3.6 (p <.0001). This is the first prospective study that quantifies the improvement in sexual function of healthy women after a 12-week Pilates program. Our findings suggest that Pilates may improve sexual function in healthy women. However, further studies with a larger sample size are needed in this field.

Global strategies for the treatment of early-stage and advanced cervical cancer.

PURPOSE OF REVIEW: Recent peer-reviewed publications on the treatment of early, locally advanced and advanced cervical cancer patients are reviewed to gain insight into the main research done in the field. RECENT FINDINGS: In early-stage patients where cure is offered to most patients, research focuses on more conservative or less morbid approaches to increase quality of life and reduce the treatment-related sexual dysfunction. No major advances have occurred for treating locally advanced disease since the introduction of concurrent chemoradiation, but efforts are directed to increase efficacy while reducing toxicity with the use of combination chemoradiation and modern radiation technologies. Molecular-targeted therapy and identification of targetable gene alterations as well as immunotherapy are actively pursued in patients with advanced disease. SUMMARY: Although global statistics indicate a trend for decreased age-standardized incidence rates, social and economical factors impede the uptake of therapeutic advances achieved as many patients have no access even to basic resources for treating cancer. The adherence to quality indicators in delivery of optimized standard concurrent chemoradiation and adherence to guidelines in cervical cancer surgery must not be underestimated. Major efforts are needed in both the scientific and social aspects of cervical cancer treatment to reduce mortality.

[Drug-induced sexual dysfunction]. / Sexuelle Klagen im Zusammenhang mit Medikamenten.

Drugs can affect sexual function through their effects on the central nervous system, the peripheral (autonomic) nervous system or through hormonal effects. As most patients do not spontaneously talk about their sex life, it is important to assess patients with critical medication for possible sexual dysfunction. Critical medication in relation to sexual function include sedative drugs, drugs that affect the central serotonin, dopamine and/ or prolactin signaling pathways as well as certain antihypertensives. It is important to note, however, that the indications for these therapies, such as schizophrenia, depression and the metabolic syndrome are themselves associated with sexual dysfunction. if a disturbing sexual dysfunction arises, treatment with the suspected drug should be discontinued and possibly changed to one with fewer adverse effects. The use of phosphodiesterase 5 inhibitors, which are largely efficacious and safe for both patients with psychiatric conditions and patients with hypertension, can be considered

Testosterone for midlife women: the hormone of desire?

Testosterone declines with aging, so most midlife women have "low" testosterone levels. Because libido also declines with aging, and distressing sexual problems peak at midlife, should midlife women with low libido and associated distress be treated with testosterone? This Practice Pearl reports clinical trial evidence, reviews the risks, and explains how testosterone might be used in a clinical setting. For women who may be considering a trial of testosterone therapy, limitations and adverse effects should be disclosed and appropriate monitoring instituted once treatment has begun.

A manifesto on the preservation of sexual function in women and girls with cancer.

Malignancies that affect females who survive cancer commonly originate in, invade, and/or metastasize to the sexual organs, including the ovaries, uterine corpus, uterine cervix, vagina, vulva, fallopian tubes, anus, rectum, breast(s), and brain. Females comprise most of the population (in number and proportion) with cancers that directly affect the sexual organs. Most females in the age groups most commonly affected by cancer are sexually active in the year before diagnosis, which includes most menopausal women who have a partner. Among female cancer survivors, the vast majority have cancers that are treated with local or systemic therapies that result in removal, compromise, or destruction of the sexual organs. Additionally, female cancer survivors often experience abrupt or premature onset of menopause, either directly with surgery, radiation, or other treatments or indirectly through disruption of female sex hormone or other neuroendocrine physiology. For many female patients, cancer treatment has short-term and long-lasting effects on other aspects of physical, psychological, and social functioning that can interfere with normal sexual function; these effects include pain, depression, and anxiety; fatigue and sleep disruption; changes in weight and body image; scars, loss of normal skin sensation, and other skin changes; changes in bodily odors; ostomies and loss of normal bowel and bladder function; lymphedema, and strained intimate partnerships and other changes in social roles. In spite of these facts, female patients who are treated for cancer receive insufficient counseling, support, or treatment to preserve or regain sexual function after cancer treatment.

Restoring testosterone levels by adding dehydroepiandrosterone to a drospirenone containing combined oral contraceptive: II. Clinical effects.

OBJECTIVES: Combined oral contraceptives (COCs) decrease androgen levels, including testosterone (T), which may be associated with sexual dysfunction and mood complaints in some women. We have shown that 'co-administration' of dehydroepiandrosterone (DHEA) to a drospirenone (DRSP)-containing COC restored total T levels to baseline and free T levels by 47%. Here we describe the effects on sexual function, mood and quality of life of such an intervention. STUDY DESIGN: This was a randomized, double-blind, placebo-controlled study in 99 healthy COC starters. A COC containing 30 mcg ethinylestradiol (EE) and 3 mg DRSP was used for three cycles, followed by six cycles of the same COC combined with 50 mg/day DHEA or placebo. Subjects completed the Moos Menstrual Distress Questionnaire (MDQ), the McCoy Female Sexuality Questionnaire and the short form of the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). Safety and tolerability, including effects on skin, were evaluated. RESULTS: The addition of DHEA induced small but significant improvements compared to placebo in the MDQ score for autonomic reactions during the menstrual (-2.0 vs. 0.71; p=0.05) and the premenstrual phase (-3.1 vs. 2.9; p=0.01) and for behavior during the intermenstrual phase (-1.4 vs. 3.6; p=0.02). A significant difference was found in the MDQ score for arousal during the premenstrual phase in favor of placebo (-5.0 vs. 1.0; p=0.01). There were no statistically significant differences between groups for the MSFQ and Q-LES-Q scores. DHEA 'co-administration' resulted in an acceptable safety profile. DHEA negated the beneficial effect of the COC on acne according to the subjects' self-assessment. CONCLUSIONS: 'Co-administration' with DHEA did not result in consistent improvements in sexual function, mood and quality of life indicators in women taking EE/DRSP. Retrospectively, the 50 mg dose of DHEA may be too low for this COC. IMPLICATIONS: A well-balanced judgment of the clinical consequences of normalizing androgens during COC use may require complete normalization of free T.