Endocrine treatment of gender-dysphoric/gender-incongruent persons: an Endocrine Society clinical practice guideline

OBJECTIVE: To update the "Endocrine Treatment of Transsexual Persons: An Endocrine Society Clinical Practice Guideline," published by the Endocrine Society in 2009. PARTICIPANTS: The participants include an Endocrine Society-appointed task force of nine experts, a methodologist, and a medical writer. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. CONSENSUS PROCESS: Group meetings, conference calls, and e-mail communications enabled consensus. Endocrine Society committees, members and cosponsoring organizations reviewed and commented on preliminary drafts of the guidelines. CONCLUSION: Gender affirmation is multidisciplinary treatment in which endocrinologists play an important role. Gender-dysphoric/gender-incongruent persons seek and/or are referred to endocrinologists to develop the physical characteristics of the affirmed gender. They require a safe and effective hormone regimen that will (1) suppress endogenous sex hormone secretion determined by the person's genetic/gonadal sex and (2) maintain sex hormone levels within the normal range for the person's affirmed gender. Hormone treatment is not recommended for prepubertal gender-dysphoric/gender-incongruent persons. Those clinicians who recommend gender-affirming endocrine treatments-appropriately trained diagnosing clinicians (required), a mental health provider for adolescents (required) and mental health professional for adults (recommended)-should be knowledgeable about the diagnostic criteria and criteria for gender-affirming treatment, have sufficient training and experience in assessing psychopathology, and be willing to participate in the ongoing care throughout the endocrine transition. We recommend treating gender-dysphoric/gender-incongruent adolescents who have entered puberty at Tanner Stage G2/B2 by suppression with gonadotropin-releasing hormone agonists. Clinicians may add gender-affirming hormones after a multidisciplinary team has confirmed the persistence of gender dysphoria/gender incongruence and sufficient mental capacity to give informed consent to this partially irreversible treatment. Most adolescents have this capacity by age 16 years old. We recognize that there may be compelling reasons to initiate sex hormone treatment prior to age 16 years, although there is minimal published experience treating prior to 13.5 to 14 years of age. For the care of peripubertal youths and older adolescents, we recommend that an expert multidisciplinary team comprised of medical professionals and mental health professionals manage this treatment. The treating physician must confirm the criteria for treatment used by the referring mental health practitioner and collaborate with them in decisions about gender-affirming surgery in older adolescents. For adult gender-dysphoric/gender-incongruent persons, the treating clinicians (collectively) should have expertise in transgender-specific diagnostic criteria, mental health, primary care, hormone treatment, and surgery, as needed by the patient. We suggest maintaining physiologic levels of gender-appropriate hormones and monitoring for known risks and complications. When high doses of sex steroids are required to suppress endogenous sex steroids and/or in advanced age, clinicians may consider surgically removing natal gonads along with reducing sex steroid treatment. Clinicians should monitor both transgender males (female to male) and transgender females (male to female) for reproductive organ cancer risk when surgical removal is incomplete. Additionally, clinicians should persistently monitor adverse effects of sex steroids. For gender-affirming surgeries in adults, the treating physician must collaborate with and confirm the criteria for treatment used by the referring physician. Clinicians should avoid harming individuals (via hormone treatment) who have conditions other than gender dysphoria/gender incongruence and who may not benefit from the physical changes associated with this treatment.

Acute joint pathology and synovial inflammation is associated with increased intra-articular fracture severity in the mouse knee.

OBJECTIVE: Post-traumatic arthritis is a frequent cause of disability and occurs most commonly and predictably after articular fracture. The objective of this investigation was to examine the effect of fracture severity on acute joint pathology in a novel murine model of intra-articular fracture. DESIGN: Low and high energy articular fractures (n=25 per group) of the tibial plateau were created in adult male C57BL/6 mice. The acute effect of articular fracture severity on synovial inflammation, bone morphology, liberated fracture area, cartilage pathology, chondrocyte viability, and systemic cytokines and biomarkers levels was assessed at 0, 1, 3, 5, and 7 days post-fracture. RESULTS: Increasing intra-articular fracture severity was associated with greater acute pathology in the synovium and bone compared to control limbs, including increased global synovitis and reduced periarticular bone density and thickness. Applied fracture energy was significantly correlated with degree of liberated cortical bone surface area, indicating greater comminution. Serum concentrations of hyaluronic acid (HA) were significantly increased 1 day post-fracture. While articular fracture significantly reduced chondrocyte viability, there was no relationship between fracture severity and chondrocyte viability, cartilage degeneration, or systemic levels of cytokines and biomarkers. CONCLUSIONS: This study demonstrates that articular fracture is associated with a loss of chondrocyte viability and increased levels of systemic biomarkers, and that increased intra-articular fracture severity is associated with increased acute joint pathology in a variety of joint tissues, including synovial inflammation, cortical comminution, and bone morphology. Further characterization of the early events following articular fracture could aid in the treatment of post-traumatic arthritis.

Viability and apoptosis of human chondrocytes in osteochondral fragments following joint trauma.

Post-traumatic arthritis is a frequent consequence of articular fracture. The mechanisms leading to its development after such injuries have not been clearly delineated. A potential contributing factor is decreased viability of the articular chondrocytes. The object of this study was to characterise the regional variation in the viability of chondrocytes following joint trauma. A total of 29 osteochondral fragments from traumatic injuries to joints that could not be used in articular reconstruction were analysed for cell viability using the fluorescence live/dead assay and for apoptosis employing the TUNEL assay, and compared with cadaver control fragments. Chondrocyte death and apoptosis were significantly greater along the edge of the fracture and in the superficial zone of the osteochondral fragments. The middle and deep zones demonstrated significantly higher viability of the chondrocytes. These findings indicate the presence of both necrotic and apoptotic chondrocytes after joint injury and may provide further insight into the role of chondrocyte death in post-traumatic arthritis.

The gonadal axis in men with schizophrenia.

The typical onset of schizophrenia during late adolescence and early adulthood has stimulated interest in the potential contribution of hypothalamo-pituitary-gonadal (HPG) axis abnormalities to this disorder. Previous investigations of reproductive hormone function in men with schizophrenia suggest diminished activity of the HPG axis. These studies have been hampered, however, by methodologic limitations. We have attempted to address these limitations by rigorous determination of gonadotropin and gonadal hormone levels, and attention to demographic and diagnostic variables. In contrast to prior studies, our results indicate that schizophrenic patients do not show statistically significant differences from healthy volunteers with respect to luteinizing hormone pulsatility, response to gonadotropin-releasing hormone challenge, and testosterone secretion. Due to the small number of subjects, however, these findings must be regarded as preliminary and warrant further study.

Some characteristics of oogenesis in the female Turkish hamster subjected to modified environments.

The hibernating female Turkish hamster (Mesocricetus brandti) was utilized for a study of possible in vivo effects of cold on oocyte maturation. Such a physiologic model offered an opportunity to analyze the ability of oocytes exposed to prolonged periods of reduced core temperature and/or light to subsequently mature to Metaphase II. Detailed observations of core temperatures, torpor/arousal, serum estradiol, and ovarian histology were made. An average incidence of 37.7% binuclearity was found in the germinal vesicle, metaphase I and II occytes of this species. Maturation to Metaphase II of total chromosome complements did not vary significantly in the experimental groups compared with the control, but aneuploidy was detected in the oocytes of animals exposed to reduced temperature or light. An effect of in vivo reduced core temperatures on oocyte chromosome complements validates many of the published in vitro studies with temperature reduction. The model presents an excellent physiologic system for perturbing and analyzing many aspects of mammalian oocyte development.

Dehydroepiandrosterone feeding prevents aortic fatty streak formation and cholesterol accumulation in cholesterol-fed rabbit.

The concentration of dehydroepiandrosterone sulfate (DHEA-S) in human plasma is higher than any other steroid. Recent evidence has suggested an inverse relationship between plasma DHEA levels and the development of coronary atherosclerosis in humans. We used the cholesterol-fed rabbit model to investigate whether DHEA feeding would diminish aortic fatty streak formation in this model. Fifteen New Zealand White rabbits were fed rabbit chow supplemented with 0.5% cholesterol (wt/wt). Seven animals were, in addition, fed DHEA, 0.5% of diet (wt/wt). Animals were sacrificed after 2 months, and the aortic involvement with fatty streaks was evaluated by computerized planimetry of Sudan IV-stained aortas and by chemical analysis of aortic wall lipids. Compared to controls, DHEA-fed animals had similar plasma levels of total, very low density lipoprotein (VLDL), low density lipoprotein (LDL), and high density lipoprotein (HDL) cholesterol, corticoids, and estrogens. DHEA-fed animals had higher plasma levels of total, VLDL, and LDL triglycerides and lower HDL triglycerides than did controls. DHEA feeding resulted in 30% and 40%, respectively, inhibition of fatty streak formation by chemical analysis and planimetry. We conclude that DHEA feeding inhibits the development of aortic fatty streaks in cholesterol-fed rabbits, independent of changes in plasma total and LDL cholesterol levels of DHEA conversion to estrogens or corticoids.

Infertility in a patient with abnormal spermatogenesis and in utero DES exposure.

A young azoospermic patient is described whose spermatogenesis reflected an abnormality of meiosis. A diagnosis of asynapsis of chromosomes during early spermatogenesis was made by cytogenetic examination of a testicular biopsy. Standard histologic examination gave no indication of this abnormality. An incidental history of intrauterine diethylstilbesterol (DES) exposure of the patient was elicited. Attention is called to the dearth of cytogenetic studies of spermatogenesis in DES-treated male progeny and the usefulness in general of meiotic cytogenetic studies for obtaining accurate diagnoses in human infertility.

Effect of vitamin A deficiency upon gonadotropin response to gonadotropin-releasing hormone.

There is a monotypic change in basal serum gonadotropin levels following retinol treatment of chronically vitamin A-deficient (VAD) male rats. The present study was undertaken to investigate the hypothesis that the specific increase in serum follicle-stimulating hormone (FSH) represents a change in gonadotrope responsiveness to gonadotropin-releasing hormone (GnRH). To this end, a test dose of GnRH was given to VAD rats pre-, 5 days post-, and 10 days postreplacement of vitamin A (PVA). In VAD rats, basal serum FSH and luteinizing hormone (LH) levels were higher than those of controls. Increased LH/testosterone ratios, both in basal levels and in the secretory response to GnRH, suggested Leydig cell hyporesponsiveness in VAD animals. Both the FSH and LH responses to GnRH were maximal at 1 h, declining thereafter. Although the absolute increments in FSH and LH 1 h after GnRH in VAD rats were greater than in controls, the percent increase in FSH tended to be lower in VAD rats and to increase after vitamin A replacement. The specific enhancement of FSH release PVA became evident only when assessing total secretion of FSH and LH after GnRH. Luteinizing hormone response to GnRH increased PVA, but not significantly, while FSH secretion after GnRH increased both 5 and 10 days PVA, times during which basal FSH levels were also increasing. These changes in FSH secretion could not be attributed either to increases in endogenous GnRH or to changes in testosterone or estradiol levels. Basal serum androgen binding protein levels, elevated in VAD animals, did not respond to the acute increases in FSH after GnRH and remained high PVA, suggesting no acute change in Sertoli cell function. Thus, the PVA increase in FSH secretion unmasks a partial inhibition of the gonadotrope present in the retinol-deficient, retinoic acid-fed male rat.

Use of a highly sensitive and specific immunoradiometric assay for detection of human chorionic gonadotropin in urine of normal, nonpregnant, and pregnant individuals.

A highly sensitive and specific two-site immunoradiometric assay (IRMA) for hCG has been developed and applied to the detection of the hormone in the urine of normal nonpregnant and pregnant individuals. The IRMA uses a solid phase coupled monoclonal antibody to the hCG beta-subunit for extraction of hormone from urine. The hCG extracted is then directly quantified by the binding of an affinity purified and radiolabeled rabbit antibody that reacts with the unique COOH-terminal peptide region of the hCG beta-subunit. The assay is capable of reliably and accurately measuring as little as 0.01 ng hCG/ml urine without interference from hLH. Assays of urine from normal men and nonpregnant women of reproductive age indicated that most individuals did not have detectable levels of hCG immunoreactivity, although a minority had minute amounts, with a mean value of approximately 0.01 ng hCG/mg creatinine. In contrast, all normal menopausal women studied had easily detectable levels of hCG immunoreactivity in their urine, with a mean value of 0.123 ng hCG/mg creatinine. A study of the excretion of hCG from three men injected with hormone for treatment of infertility indicated that after the first 24 h, hCG was cleared with a single exponential rate and was detectable to a level of 0.01 ng/ml. Application of the IRMA to measurements of hCG in the urine of two artificially inseminated patients indicated that the method was capable of detecting pregnancy as early as 9 days postovulation. The extreme sensitivity and specificity of the IRMA for urinary hCG in conjunction with the simplicity of assay performance and specimen collection should provide a substantial advantage over currently available methods for detection of early pregnancy and tumor monitoring.

The effect of delta 1-testolactone on serum testosterone and estradiol in the adult male rat.

delta 1-Testolactone, an androgen derivative without intrinsic hormonal action, is known to block the aromatization of androgens to estrogens. This study was designed to assess its effect upon serum testosterone (T) and estradiol (E2) in the adult male rat. By itself, testolactone (TL) did not affect T/E2 levels in the dosages utilized. Daily injections of human chorionic gonadotropin (hCG) for 15 days caused a tenfold rise in serum T, although there was no increase in serum E2. When given along with hCG, TL did not alter the Leydig cell response. However, pretreatment of animals with TL increased the testicular response to hCG over that of saline-treated animals. Studies were also carried out to delineate the sources of estrogen in the adult male rat. These experiments demonstrate that (1) the majority of E2 is not testicular in origin but is derived from the adrenal; (2) the conversion of androgen precursors to E2 in the rat is not affected by TL; and (3) in spite of no demonstrable inhibition of E2 production, TL causes an increased Leydig cell responsiveness to hCG.

Penetration of the zona pellucida of nonliving human oocytes by human spermatozoa in vitro.

In an in vitro assay human spermatozoa penetrated the zona pellucida of 38.8% of 773 human oocytes recovered from the ovaries of cadavers. Zona penetration was not observed until 8 hours had elapsed. Oocytes examined with the electron microscope were surrounded mainly by sperm with intact acrosomes, but contained sperm in the zona and perivitelline space which had lost the outer acrosomal membrane and acrosomal contents. Sperm entry into the ooplasm was never observed. Spermatozoa from 11 of 16 patients with suspected infertility penetrated the zona, although the penetration rate was lower than that with sperm from fertile donors (12.9% versus 46.4%). When oocytes were incubated with mixed suspensions containing equal numbers of motile sperm from donors and patients, the donor sperm (identified by a fluorescent label) penetrated 50.0% and the patient sperm only 12.7%. These data suggest that human sperm penetrate the zona pellucida of nonliving human oocytes and mature living ova in a similar manner. This method is a potential diagnostic and investigative tool which avoids the ethical and technical problems associated with human in vitro fertilization.