RF9: May it be a new therapeutic option for hypogonadotropic hypogonadism?

Hypogonadotropic hypogonadism (secondary hypogonadism), congenital or acquired, is a form of hypogonadism that is due to problems with either the hypothalamus or pituitary gland affecting gonadotropin levels. Pulsatile secretion of gonadotropin-releasing hormone (GnRH) by hypothalamus is a primer step to initiate the release of pituitary gonadotropins. Kisspeptin and gonadotropin-inhibitory hormone (GnIH) are accepted as two major players in the activation and inhibition of GnRH regarding the neuroendocrine functioning of the hypothalamic pituitary gonadal axis. Kisspeptin is known as the most potent activator of GnRH. Regarding the inhibition of GnRH, RF-amide-related peptide-3 (RFRP-3) is accepted as the mammalian orthologue of GnIH in avian species. RF9 (1-adamantane carbonyl-Arg-Phe-NH2) is an antagonist of RFRP-3/GnIH receptor (neuropeptide FF receptor 1 (NPFFR1; also termed as GPR147). In recent years, several studies have indicated that RF9 activates GnRH neurons and gonadotropins in a kisspeptin receptor (Kiss1r, formerly known as GPR54) dependent manner. These results suggest that RF9 may have a bimodal function as both an RFRP-3 antagonist and a kisspeptin agonist or it may be a kiss1r agonist rather than an RFRP-3/GnIH receptor antagonist. These interactions are possible because Kisspeptin and GnIH are members of the RF-amide family, and both possibilities are not far from explaining the potent gonadotropin stimulating effects of RF9. Therefore, we hypothesize that RF9 may be a new therapeutic option for the hypogonadotropic hypogonadism due to its potent GnRH stimulating effects. A constant or repeated administration of RF9 provides a sustained increase in plasma gonadotrophin levels. However, applications in the same way with GnRH analogues and kisspeptin may result in desensitization of the gonadotropic axis. The reasons reported above contribute to our hypothesis that RF9 may be a good option in the GnRH stimulating as a kisspeptin agonist. We suggest that further studies are needed to elucidate the potential effects of RF9 in the treatment of the hypogonadotropic hypogonadism.

Transition in Pediatric and Adolescent Hypogonadal Girls: Gynecological Aspects, Estrogen Replacement Therapy, and Contraception.

Hypogonadism may be suspected if puberty is delayed. Pubertal delay may be caused by a normal physiological variant, by primary ovarian insufficiency (Turner syndrome), or reflect congenital hypogonadotropic hypogonadism (HH; genetic) or acquired HH (brain lesions). Any underlying chronic disease like inflammatory bowel disease, celiac disease, malnutrition (anorexia or orthorexia), or excessive physical activity may also result in functional HH. Thus, girls with delayed puberty should be evaluated for an underlying pathology before any treatment, including oral contraception, is initiated. Estrogen replacement is important and natural 17ß-estradiol, preferably transdermally, is the preferred choice, whereas the oral route can be used as an alternative depending on patient preference and compliance. Sexual activity is often delayed in the hypogonadal adolescent girl. In the adolescent hypogonadal girl, hormone replacement therapy (HRT) most likely has been initiated at the time she becomes sexually active. If a risk of unwanted pregnancy cannot be ruled out, there is a need to consider contraception. This consideration does not contradict the principles of HRT but can be included as a part of the substitution, e.g. oral contraceptives containing 17ß-estradiol or a progestogen intrauterine device combined with continuous 17ß-estradiol (transdermal or oral).

Hypogonadism in male thalassemia major patients: pathophysiology, diagnosis and treatment.

Failure of pubertal growth, delay or absence of sexual development, infertility and sexual dysfunction due to hypogonadism and defective spermatogenesis are frequent and well recognized disturbances among male patients with transfusion dependent (TD) thalassaemia major (ß-thal). These problems are attributed mainly to the damage caused by chronic anaemia and the deposition of excess iron in the pituitary gland and testicles. This is a short review of male pubertal disorders in patients with ß-thal written by pediatric endocrinologists and haematologists with an interest and active involvement, in the diagnosis and management of these complications in this group of patients. A vigilant clinical evaluation of growth and puberty, as well as an appropriate hormonal evaluation in poly-transfused (TD ß-thal) patients is strongly recommended for early detection and treatment of endocrine dysfunction. Of crucial importance also, is the implementation of an efficient chelation regime from early life, to prevent severe iron load and permanent damage to the endocrine glands, particularly those responsible for gonadal function.

Gonadal dysfunction in adult male patients with thalassemia major: an update for clinicians caring for thalassemia.

INTRODUCTION: Hypogonadism is the most frequently reported endocrine complication, affecting 40%-80% of thalassemia major (TM) patients. The prevalence and severity of hypogonadism in TM varies among studies, depending on patients' age, genotype, transfusion frequency and starting age and efficiency of iron chelation. Areas covered: The diagnosis requires careful clinical assessment and appropriate laboratory testing. Its management is more complex compared to other 'classical' causes of hypogonadism because of multiple associated disorders (cardiac, hepatic and endocrine) and other contributing factors basically iron overload and iron toxicity. Expert commentary: Early recognition and treatment of hypogonadism in TM patients is most important to prevent late complications and to enhance the chances of parenthood. The goal of management is to restore deficient glandular function. If fertility is the issue and the testis is under-stimulated because of gonadotropin deficiency, it is possible to induce or restore spermatogenesis with exogenous gonadotropins in some patients. Assisted reproductive techniques may supplementary help to overcome previously untreatable causes of male infertility. These positive achievements should encourage health care providers to pay closer attention to the reproductive health of TM patients. This would involve the collaboration of clinicians caring for thalassemia with endocrinologists and specialists in assisted reproductive technologies.

A Perspective on Middle-Aged and Older Men With Functional Hypogonadism: Focus on Holistic Management.

Context: Middle-aged and older men (≥50 years), especially those who are obese and suffer from comorbidities, not uncommonly present with clinical features consistent with androgen deficiency and modestly reduced testosterone levels. Commonly, such men do not demonstrate anatomical hypothalamic-pituitary-testicular axis pathology but have functional hypogonadism that is potentially reversible. Evidence Acquisition: Literature review from 1970 to October 2016. Evidence Synthesis: Although definitive randomized controlled trials are lacking, evidence suggests that in such men, lifestyle measures to achieve weight loss and optimization of comorbidities, including discontinuation of offending medications, lead to clinical improvement and a modest increase in testosterone. Also, androgen deficiency-like symptoms and end-organ deficits respond to targeted treatments (such as phosphodiesterase-5 inhibitors for erectile dysfunction) without evidence that hypogonadal men are refractory. Unfortunately, lifestyle interventions remain difficult and may be insufficient even if successful. Testosterone therapy should be considered primarily for men who have significant clinical features of androgen deficiency and unequivocally low testosterone levels. Testosterone should be initiated either concomitantly with a trial of lifestyle measures, or after such a trial fails, after a tailored diagnostic work-up, exclusion of contraindications, and appropriate counseling. Conclusions: There is modest evidence that functional hypogonadism responds to lifestyle measures and optimization of comorbidities. If achievable, these interventions may have demonstrable health benefits beyond the potential for increasing testosterone levels. Therefore, treatment of underlying causes of functional hypogonadism and of symptoms should be used either as an initial or adjunctive approach to testosterone therapy.

Multi-Institutional Survey of Medical Treatment for Late-Onset Hypogonadism in Japan.

The adequate criteria for late-onset hypogonadism (LOH) diagnosis, including serum testosterone levels, type (total or free testosterone) and duration of androgen replacement therapy, and evaluations of treatment effectiveness remain controversial. To evaluate the current status of medical treatment for LOH in Japan, the first nationwide survey were performed. A total of 35 questionnaires answered by urologists in high-volume facilities were analyzed. The median numbers of patients with hypogonadism-related symptoms per month were 10. Aging Male Symptom Score, International Index of Erectile Function, and International Prostate Symptom Score questionnaires were widely used for questionnaires. The diagnostic criteria for LOH varied. Among the patients who presented with hypogonadism-related symptoms, the mean proportion of patients undergoing treatment for LOH was 62.3%. In Japan, LOH was treated not only with testosterone enanthate injections or testosterone ointment but also with Kampo medicine. In many facilities, LOH treatment effectiveness was assessed after a 3-month period. Efficacy was assessed in different ways. Treatment effectiveness rate ranged from 30% to 80%. The duration of LOH treatment was not fixed and was established individually by both the patient and treating physician. This study showed that the real clinical practices for LOH are very diverse, and a general consensus is needed.

[Induced differentiation of stem cells into androgen-secreting cells].

Leydig cells are the major source of androgens in males. Stem cells can be induced to differentiate into androgen-secreting Leydig like cells, whose functions are regulated by the hypothalamus and pituitary, so that they precisely secret the necessary hormones to maintain physiological function. Therefore, the establishment of an effective protocol to induce the differentiation of stem cells into androgen-secreting cells is very helpful for the treatment of hypogonadism caused by abnormalities of Leydig cells. This review outlines the recent findings concerning the differentiation of stem cells into androgen-secreting cells.

Endocrinopathies, metabolic disorders, and iron overload in major and intermedia thalassemia: serum ferritin as diagnostic and predictive marker associated with liver and cardiac T2* MRI assessment.

INTRODUCTION: Endocrinopathies and metabolic disorders-characterized ß thalassemic (ßT) patients and the prevention and treatment of these comorbidities are important targets to be achieved. The aim of the study was to analyze the diagnostic and prognostic role of ferritin for endocrinopathies and metabolic disorders in ßT patients. The ability of iron chelators to treat iron overload and to prevent or reverse metabolic disorders and endocrinopathies was also evaluated. PATIENTS AND METHODS: Seventy-two ßT patients were treated with different chelation strategies during the study. Receiver operating characteristics analysis was employed to calculate the area under the curve for serum ferritin to find the best cutoff values capable of identifying endocrine dysfunction in thalassemic patients. Kaplan-Meier curves were generated to assess the incidence of endocrinopathy. Adjusted risk estimates for endocrinopathy were calculated using univariate followed by multivariate Cox proportional hazard regression analysis. RESULTS: High ferritin levels were observed in patients with hypothyroidism [1500 (872.5-2336.5) µg/L], hypogonadism [878 (334-2010) µg/L], and in patients with hypoparathyroidism or osteoporosis [834 (367-1857) µg/L]. A strict correlation between ferritin and T2* magnetic resonance imaging of heart (r = -0.64; P:0.0006) and liver (r = -0.40; P:0.03) values was observed. Patients with ferritin values above 1800 µg/L experienced a significantly faster evolution to hypothyroidism [log-rank (χ(2) ):7.7; P = 0.005], hypogonadism [log-rank (χ(2) ):10.7; P = 0.001], and multiple endocrinopathies [log-rank (χ(2) ):5.72; P = 0.02]. Ferritin predicted high risk of endocrine dysfunction independently of confounding factors (HR:1.23; P < 0.0001). The intensification of chelation therapy led to an amelioration of hypothyroidism. CONCLUSIONS: Ferritin represents a prognostic marker for ßT patients and a predictive factor for progression to endocrine dysfunctions. Intensive chelation therapy allows the reversibility of hypothyroidism.

[Risks and benefits: new concepts of treatment of late-onset hypogonadism].

Late-onset hypogonadism (LOH) is a clinical and bio-chemical syndrome associated with advancing age in males and seriously affects the quality of life of some of the patients. A classical therapeutic option for LOH is testosterone supplementary treatment (TST). Its effectiveness has been verified, whereas its long-term safety remains to be further evaluated. With deeper insights into LOH, many new therapeutic strategies have been proposed, which include the treatments with gonadotropins, testosterone precursors (such as dehydroepiandrosterone [DHEA]), non-aromatizable androgens (such as dihydrotestosterone [DHT]), antiestrogens (such as aromatase inhibitors and estrogen receptor antagonists), and Chinese medicine. Meanwhile, studies on the transplantation of Leydig stem cells, selective androgen receptor modulators (SARMs), and selective estrogen receptor beta (ERbeta) agonists have shed new light on the treatment of LOH.

Alternative treatment modalities for the hypogonadal patient.

Testosterone (T) deficiency syndrome (TDS) is a prevalent condition, commonly managed with exogenous T. Despite an abundance of T formulations, alternative treatments are often sought for various reasons. To evaluate outcomes of alternative therapies, a PubMed search was performed of all publications that included men with TDS from 1990 through October 2013, with results summarized. Proposed mechanisms of action were also reviewed to provide a pathophysiologic basis for reported outcomes. Nonpharmacologic therapies that increase endogenous T are weight loss, exercise, and varicocelectomy, while medications used off-label include aromatase inhibitors, human chorionic gonadotropin, and selective estrogen receptor modulators. All reported therapies increase T, while changes in estradiol and adverse events vary by therapeutic class. Although limited data preclude direct comparisons between therapies, exercise and weight loss alone or in combination with medications may be considered first line. The role for surgical therapy in TDS remains undefined and requires further study.

[Therapeutic issues concerning male fertility]. / Enjeux thérapeutiques en fertilité masculine.

Men reproductive health has long been ignored although it is responsible for 50% of couple's infertility. However, in recent years, the understanding of endocrine physiology underlying testis development and spermatogenesis has enabled the development of new therapeutic strategies. Some concern the management of male infertility. Others are dealing with finding an effective male contraceptive. In this review, we first present the management of infertility, in patients with congenital hypogonadotropic hypogonadism. We then describe the major improvements for Klinefelter patient's infertility. Finally, we review the different hormonal and non-hormonal methods for male contraception, currently in development. Efficacy and safety of the some non-hormonal methods remain to be demonstrated so far in humans.

[Andropause and testosterone deficiency: how to treat in 2012?]. / Andropause et carence en testostérone: le point en 2012.

Age-related hypogonadism is a clinical syndrome defined as a low serum testosterone level (< 11 nmol/l) with precise clinical symptoms: diminished libido, erectile dysfunction, and loss of morning erection. Testosterone supplementation has been shown to have a beneficial effect on muscle and fat mass as well as on bone mineral density, with more conflicting effects observed on muscle strength, sexual function, mood and quality of life. In spite of an inverse relationship between testosterone levels and various cardiovascular risk factors (obesity, insulin resistance and type 2 diabetes mellitus), there is no evidence of a positive effect of testosterone replacement therapy towards these risk factors. So far, the long-term safety of testosterone replacement therapy has not been established. Evidence has been found that testosterone replacement therapy has a causative and worsening role in prostate cancer urging not to treat patients with a history of prostate cancer. Finally, patients with high cardiovascular risk, including those with congestive heart failure, should not be treated.

Pituitary iron and volume predict hypogonadism in transfusional iron overload.

Hypogonadism is the most common morbidity in patients with transfusion-dependent anemias such as thalassemia major. We used magnetic resonance imaging (MRI) to measure pituitary R2 (iron) and volume to determine at what age these patients develop pituitary iron overload and volume loss. We recruited 56 patients (47 with thalassemia major, five with chronically transfused thalassemia intermedia and four with Blackfan-Diamond syndrome) to have pituitary MRIs to measure pituitary R2 and volume. Hypogonadism was defined clinically based on the timing of secondary sexual characteristics or the need for sex hormone replacement therapy. Patients with transfusional iron overload begin to develop pituitary iron overload in the first decade of life; however, clinically significant volume loss was not observed until the second decade of life. Severe pituitary iron deposition (Z > 5) and volume loss (Z < -2.5) were independently predictive of hypogonadism. Pituitary R2 correlated significantly with serum ferritin as well as liver, pancreatic, and cardiac iron deposition by MRI. Log pancreas R2* was the best single predictor for pituitary iron, with an area under the receiving operator characteristic curve of 0.88, but log cardiac R2* and ferritin were retained on multivariate regression with a combined r(2) of 0.71. Pituitary iron overload and volume loss were independently predictive of hypogonadism. Many patients with moderate-to-severe pituitary iron overload retained normal gland volume and function, representing a potential therapeutic window. The subset of hypogonadal patients having preserved gland volumes may also explain improvements in pituitary function observed following intensive chelation therapy.

The effects and prospects of the integration of traditional Chinese medicine and Western medicine on andrology in China.

Andrology has a long history in traditional Chinese medicine (TCM) discussions concerning andropathies, and documentation of relevant therapeutic methods abound in the ancient literature on TCM. Integrated treatment combining TCM and Western medicine has seen both broad and in-depth development, with formidable status in the field of modern andrology in China. This article attempts to demonstrate the unique advantage of integrated treatment in the therapy of andropathies through a review of the ancient literature on andrology in the field of TCM and on the integrative treatment of prostatic diseases, sexual dysfunction, male infertility and late-onset hypogonadism. There is a need for the advancement of a medical theory that integrates TCM and Western medicine practices to create a new therapeutic system with standardized therapeutic and evaluative protocols for diseases involving male sexual health.

Improvement in reproductive parameters in hypogonadal female mice by regulated gene replacement therapy in the central nervous system.

One of the challenges of gene targeting is to achieve regulated transgene expression in specific target cells. The hypogonadal (hpg) mice are genetically deficient in hypothalamic gonadotropin-releasing hormone (GnRH) production due to a deletion in the GnRH gene, resulting in hypogonadotropic hypogonadism. Here we show an improvement in reproductive parameters of adult female homozygous hpg mice by direct infusion into the hypothalamic preoptic area (POA) of a herpes simplex virus (HSV)-based amplicon vector containing a 13.5 kb genomic fragment encoding the GnRH gene together with its cognate promoter and regulatory elements. Following vector injection, GnRH-expressing neurons were detected in the POA, and pituitary and plasma gonadotropin levels as well as ovarian and uterine weights increased. In addition, a subset of injected hpg mice demonstrated cyclic estrous changes, consistent with regulated control of GnRH production. Administration of kisspeptin-10 resulted in an increase in plasma luteinizing hormone levels, further supporting appropriate regulation of the introduced GnRH transgene. These findings indicate that delivery of the GnRH gene resulted in selective neuronal expression of GnRH and regulated hypothalamic GnRH release. To our knowledge, this is the first example of the correct targeting of a gene under its cognate promoter to neurons resulting in selective and regulated synthesis of a biologically active peptide, and thus may have a wide range of applications in the treatment of human disorders.

Reversibility of hypogonadotropic hypogonadism in a patient with the juvenile form of hemochromatosis.

OBJECTIVE: To report a case of complete reversibility of hypogonadotropic hypogonadism with intensive venesection treatment in juvenile hemochromatosis. DESIGN: Case report. SETTING: Endocrine department of Hippocrateion Hospital of Athens. PATIENT(S): A 25-year-old man who presented with hypogonadotropic hypogonadism and severe iron overload due to juvenile hemochromatosis and who was initially treated with phlebotomies and androgen substitution. INTERVENTION(S): Intensification of chelation therapy. MAIN OUTCOME MEASURE(S): Clinical evaluation, serum ferritin concentration, and biochemical assessment of pituitary function were performed periodically. RESULT(S): One year after normalization of serum ferritin levels and transferrin saturation was achieved, he became eugonadal. CONCLUSION(S): We believe that hypogonadotropic hypogonadism in juvenile hemochromatosis may be reversible by a consequent venesection therapy probably because treatment was intensive and promptly introduced at a young age.

Management of surgically hypogonadal patients unable to take sex hormone replacement therapy.

Lifestyle changes in diet, exercise and the environment may help to prevent or ameliorate hot flashes and low bone density in men and women after surgical castration. Conventional medications, including megestrol acetate, SSRIs or clonidine, may improve hot flashes but may have limiting side effects. Some complementary and alternative approaches, including black cohosh, vitamin E, and soy products, work as well as placebo to decrease hot flashes and may be helpful, because they have low toxicity. Acupuncture and neurontin are promising but must be studied further. With regards to the prevention of osteoporosis and fractures in men and women, bisphosphonates are the most potent of the currently available agents; calcitonin is less effective. PTH has a large beneficial effect but is not yet available and is less well studied. In women, continued sexual intercourse and use of vaginal lubricants and moisturizers help to minimize symptoms of vaginal atrophy but do not ameliorate urinary symptoms. Low dose local estrogen treatment is a promising approach for the latter complaints.

Ovulation induction with pulsatile gonadotropin-releasing hormone (GnRH) or gonadotropins in a case of hypothalamic amenorrhea and diabetes insipidus.

Hypothalamic amenorrhea is a treatable cause of infertility. Our patient was presented with secondary amenorrhea and diabetes insipidus. Cortisol and prolactin responded normally to a combined insulin tolerance test (ITT) and thyrotropin-releasing hormone (TRH) challenge, while thyroid-stimulating hormone (TSH) response to TRH was diminished, and no response of growth hormone to ITT was detected. Both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels increased following gonadotropin-releasing hormone (GnRH) challenge. No response of LH to clomiphene citrate challenge was detected. Magnetic resonance imaging findings demonstrated a midline mass occupying the inferior hypothalamus, with posterior lobe not visible and thickened pituitary stalk. Ovulation induction was carried out first with combined human menopausal gonadotropins (hMG/LH/FSH) (150 IU/day) and afterwards with pulsatile GnRH (150 ng/kg/pulse). Ovulation was achieved with both pulsatile GnRH and combine gonadotropin therapy. Slightly better results were achieved with the pulsatile GnRH treatment.

Treatment of HIV related weight loss.

AIDS: Weight loss is a significant problem with HIV and AIDS patients. The definition of wasting syndrome is provided. Men and women do not lose weight and body mass in the same way; the differences between the genders are reviewed. Treatment includes insuring an adequate oral intake of calories, correcting malabsorption problems, and using anabolic steroids to rebuild body mass. Resistance exercises may also be helpful.^ieng

Hypogonadism in Prader-Willi syndrome.

Prader-Willi syndrome is characterized by eating abnormalities, infantile hypotonia, obesity, mental retardation, and hypogonadism. The causation of hypogonadism varies. We describe a patient with Prader-Willi syndrome whose hypogonadism is secondary to a hypothalamic defect. Individualization of patients with this syndrome is suggested. Based on the particular hormonal abnormality identified, a treatment plan can be constructed. Cryptorchidism should be approached in the usual fashion.