Hypogonadotropic Hypogonadism Associated With Leptin and LeptinR Mutations
The adipocyte-specific hormone, leptin, the product of the obese ob gene, acts on the hypothalamus to control appetite and energy expenditure 102 . Leptin acts through the leptin receptor leptin-R , a single transmembrane-domain receptor of the cytokine-receptor family 103 . In 1997, Montague reported the first consanguineous family with two very obese prepubertal children who had congenital leptin deficiency 104 . The two cousins were homozygous for a frameshift mutation in the leptin gene....
Sexual Dysfunction
Sexual function is frequently impaired by chronic renal failure 55 and is only partly reversed by transplantation, although few well-controlled studies are available. Contributory factors include vascular failure, pelvic autonomic neuropathy, antihypertensives particularly centrally acting agents and beta blockers , and other medications, together with additive effects of age, depression, and general debility. Uremic sexual function is not consistently improved with androgen therapy 200-400 mg...
Neonatal Leydig Cells
Just after birth, the number of Leydig cells again increases to a peak at 2 to 3 mo of age, contributing to a second surge in plasma testosterone levels. At this stage, Leydig cells contain abundant SER membranes and mitochondria, as well as varying amounts of lipid droplets 4,24-27 . In the neonatal testis, fetal Leydig cells persist through at least 3 mo after birth. Postnatal increase in the number of these cells most likely results from recruitment of interstitial precursor cells. After...
How Do We Monitor Androgen Replacement Therapy
In hypogonadal men, most of the symptoms of androgen deficiency are alleviated with androgen replacement. To determine the dose of testosterone to be administered, serum testosterone levels should be measured at appropriate times after drug administration, based on the PK characteristics of the specific preparation. For example, serum testosterone levels peak 12-16 h after application of testosterone patches and return toward baseline by 24 h. Monitoring is thus done approx 12 h after...
Cyclophosphamide
Rivkees and Crawford 5 published a meta-analysis of 30 studies that examined gonadal function after various chemotherapy regimens, which included 116 men who had been treated with cyclophosphamide alone. Gonadal function and or histology were assessed by several different methods semen analysis, basal LH and follicle-stimulating hormone FSH levels, and testicular biopsy were the most commonly used. Of the 116 patients, 52 45 had evidence of testicular dysfunction after treatment. The finding of...
ROLE OF INTRINSIC GnRH DEFICIENCY IN MEDIATING LOWAMPLITUDE LH SECRETION
Experiments in the male mouse and rat support an important, but not exclusive, role of GnRH-deficient hypogonadotropism in the hypoandrogenemia of aging 41-44 . Evidence to this end includes 1 decreased castration-, naloxone-, and restraint stress-induced LH release in the older rodent 24,42,45-47 2 diminished in vivo LH pulse amplitude in senescent animals 43,48 3 reduced in vitro hypothalamic GnRH secretion 49,50 4 altered GnRH neuronal synaptology 51 5 preservation of the stimulatory...
Diagnosis Yzd
Since the description by Cushing at the beginning of the 20th century, it is well known that hypogonadism is common in active Cushing's disease 62 . Men have loss of libido, impotence, oligospermia, and histological damage to the testes. Basal LH and FSH levels are commonly decreased, the response to GnRH is impaired, and testosterone levels are low. However, hypogonadism occurs with other clinical features see Table 3 secondary to chronically elevated cortisol production 47,63 . When Cushing's...
Factors Regulating GnRH secretion
The current view is that central inhibition of GnRH release results in a prepubertal quiescence of gonadotropin secretion, and the onset of puberty results from the removal of this central restraint 28 . Mechanisms related to the control of the onset of puberty have been extensively studied in various rodent models. However, in rodents, the interval between infancy and puberty is condensed, and these two developmental phases cannot be separated by a clearly demarcated juvenile phase of...
Fertility In Men With Other Enzymatic Deficiencies In Steroid Synthesis
CAH can also be caused by enzyme deficiencies other than 21-hydroxylase deficiency see Fig. 1 . The first two enzymes in steroid synthesis 30-hydroxysteroid dehydrogenase and 17a-hydroxylase 17,20-lyase and the intracellular cholesterol transport protein StAR , are present in both adrenals and gonads. A deficiency of these enzymes or in the StAR protein leads to cortisol and aldosterone deficiency and insufficient gonadal production of sex steroids. In the male patient, this results in prenatal...
Injectables
Testosterone enanthate TE and cypionate are testosterone esters administered by biweekly or triweekly deep im injection. The usual recommended dose for hypogo-nadal men is 200 mg in 1 mL oil administered every 2 wk. The pharmacokinetics PK of injectable testosterone preparations have been carefully studied 73,74 , and the PK of TE is shown in Fig. 2. Serum testosterone levels peak within 1 to 3 d after administration, and gradually decline to a trough after 2 to 3 wk. In many subjects, the peak...
ExerciseHypogonadal Males Basal Hormonal Responses
Retrospective comparative studies examining isolated, single blood samples have found lower testosterone levels in chronically endurance-trained males. The subjects in those studies were typically distance runners who had been involved with the physical-training aspects of their sport for 1 to 15 yr. In those studies, total and free-testosterone levels in the endurance-trained men were only 60-85 of the levels of matched sedentary controls 7,35,54,56-58 . Many of the early studies reporting...
Other LifestyleDietary Factors Affecting the Adult Male
The preceding section dealing with scrotal temperature obviously applies as much to sedentary lifestyles outside, as well as inside, of the workplace. Probably the most important other factors are dietary habits, particularly obesity and alcohol intake, smoking, stress, and recreational sporting drug use. Unlike the well-established relationship between caloric intake and maintenance of menstrual cycles in women, there is no such clear relationship in men regarding sperm production and semen...
Anemia
The anemia of end-stage renal failure has multiple contributory factors, including EPO deficiency, toxic inhibitors of EPO action, androgen deficiency, micronutrient deficiency iron, folate, and pyridoxine , blood loss, and hemolysis 81 . Although the balance between these remains conjectural, EPO deficiency is a major factor 82 , and androgen therapy has consistent effects on EPO secretion and hemoglobin concentrations 83 . Endogenous testosterone is an important physiological determinant of...
GnRH Deficient
Fig. 5. Schematic drawing of the hypothalamic-pituitary-gonadal axis in a normal adult male and in congenital hypogonadotropic hypogonadism. Biochemical Studies. Despite variation in the clinical phenotype of CIHH men, their biochemical findings are similar. By definition, all patients have T levels in the hypogonadal range. Gonadotropins are low normal in all subjects, which, in the setting of low T levels, indicate hypogonadotropic hypogonadism see Figs. 5 and 6 . Interestingly, mean LH and...
References Bhi
1. White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev 2000 21 245-291. 2. Jaaskelainen J, Kiekara O, Hippelainen M, Voutilainen R. Pituitary gonadal axis and child rate in males with classical 21-hydroxylase deficiency. J Endocrinol Invest 2000 23 23-27. 3. Urban MD, Lee PA, Migeon CJ. Adult height and fertility in men with congenital virilizing adrenal hyperplasia. N Engl J Med 1978 299 1392-1396. 4. Wuesthof AR, Willig RP, Schulze W, Hoepffner W,...
High Prevalence Of Androgen Deficiency In Hivinfected Men And Women
Early studies 1-4 suggested that as many as 30-50 of HIV-infected men have serum testosterone levels that are below the lower limit of the normal range for healthy, young men. For instance, Dobs et al. 1 reported that 50 of HIV-infected men had low testosterone concentrations. Grinspoon et al. 2 described a reduction in free testosterone levels in 49 of HIV-infected men with AIDS wasting. In a prospective survey 5 conducted in 1998 during the early days of protease inhibitor therapy, we...
TIME minutes
Fig. 2. Frequent blood sampling every 10 min for 24 h for luteinizing hormone LH in a normal man and a man with idiopathic hypogonadotropic hypogonadism IHH . A Normal adult male pattern of gonadotropin-releasing hormone GnRH secretion with high amplitude LH pulsations 10 pulses in 24 h , normal serum testosterone levels, and normal testicular volume B Apulsatile pattern of GnRH secretion in an IHH male as assessed by a complete absence of endogenous LH pulsations, low serum testosterone...
Therapy Uif
Gonadal impairment secondary to nonpituitary intrasellar and parasellar masses may recover after treatment of the lesion. The choice of treatment depends on the nature of the disease. However, surgery represents the first option in most cases. Surgical treatment generally involves trans-sphenoidal decompression of the mass, when possible, attempting to limit damage and restore normal function of the pituitary gland. Contraindications to the trans-sphenoidal approach include dumb-bell tumors and...
References Gvq
1. Kaplan SL, Grumbach MM. The ontogenesis of human foetal hormones. II. Luteinizing hormone LH and follicle stimulating hormone FSH . Acta Endocrinol Copenh 1976 81 808-829. 2. Castillo RH, Matteri RL, Dumesic DA. Luteinizing hormone synthesis in cultured fetal human pituitary cells exposed to gonadotropin-releasing hormone. J Clin Endocrinol Metab 1992 75 318-322. 3. Sullivan KA, Silverman AJ. The ontogeny of gonadotropin-releasing hormone neurons in the chick. Neuroendocrinology 1993 58...
Spermatogenesis Stimulation
The induction of spermatogenesis in patients with hypogonadotropic hypogonadism requires testicular stimulation with GnRH or gonadotropins. Various preparations are available see Table 1 to reach this goal, each with advantages and disadvantages. Because the maturation of spermatogonia to mature sperm takes approx 70 d, the first sperm usually do not appear in the ejaculate for at least 3 mo, but it may take 2 yr for patients with congenital hypogonadotropic hypogonadism to become sperm...
References Eqz
1. Weinbauer GF, Gromoll J, Simoni M, Nieschlag E. Physiology of testicular function. In Nieschlag E, Behre HM, eds. Andrology Male Reproductive Health and Dysfunction, 2nd ed. Springer, Berlin, 2000, pp. 23-61. 2. Nieschlag E, Simoni M, Gromoll J, Weinbauer GF. Role of FSH in the regulation of spermatogenesis clinical aspects. Clin Endocrinol 1999 51 139-146. 3. Behre HM, Yeung CH, Holstein AF, Weinbauer GF, Gassner P, Nieschlag E. Diagnosis of male infertility and hypogonadism. In Nieschlag...
Hematocrit Hemoglobin and Liver Function Tests
Androgens increase erythropoiesis EPO by acting directly on stem cell proliferation and through its action on the kidneys to stimulate EPO production 69 . Androgen therapy in hypogonadal and eugonadal men results in elevation of hematocrit and hemoglobin 17,40,55 . The increases in hemoglobin and hematocrit occur within 3 mo, but progressive increases are uncommon, unless the dose of testosterone is adjusted upward or another cause for polycythemia is also present. Direct dose-response...
Introduction Khp
Klinefelter's syndrome KS is the most common sex chromosome disorder in men, affecting roughly 1 in 400-600 men throughout all ethnic groups 1,2 . It is also the most common cause of primary testicular failure, resulting in impairments in both spermatogenesis and testosterone production. The hypogonadism associated with KS can range from mild to severe, leading to a marked variation in clinical presentation. Men with KS possess at least one additional or supernumerary X chromosome, resulting in...
Testosterone Shbg And Obesity
Correlations Between Sex Hormone-Binding Globulin and Measures of Adiposity in Men Relation Between Sex Hormone-Binding Globulin and Author No. of Men Body Mass Index Waist-to-Hip Ratio Correlations Between Sex Hormone-Binding Globulin and Measures of Adiposity in Men Relation Between Sex Hormone-Binding Globulin and Author No. of Men Body Mass Index Waist-to-Hip Ratio determine whether visceral fat is more closely linked to low testosterone than is total body fat, but results have been...
Pathophysiology Of Klinefelters Syndrome
Most cases of KS occur through sporadic chromosomal nondisjunction during parental gametogenesis in either the sperm or the egg. A seminal study using DNA probes to X chromosome restriction-site polymorphisms demonstrated that in one series of 32 individuals with KS the additional X chromosome was of paternal origin in 17 53 of cases and of maternal origin in 14 44 of cases and resulted from a postzygotic mitotic error in 1 3 case see Table 1 10 . Because these are sporadic errors in...
Accelerated LH Pulse Frequency in the Aging Male
A basic, unresolved mechanistic issue is whether aging causes a primary hypothalamic disturbance that enforces a high frequency of GnRH pulses and or whether low bioavailable testosterone concentrations elevate LH pulse frequency via feedback withdrawal 27,35-37,40,55 . This query is central to contemporary physiological assessments of aging, inasmuch as earlier investigations in healthy young men document that 1 infusion of testosterone or a nonaromatizable androgen suppresses LH pulse...
Clinical Features Of Klinefelters Syndrome
The clinical manifestations of KS are those of prepubertal androgen deficiency and infertility. Because testicular failure occurs before puberty, the developmental changes Fig. 2. An individual with Klinefelter's syndrome. Note tall body proportions, gynecomastia, relative paucity of facial and body hair, and small testis. Photos courtesy of Dr. C. Alvin Paulsen. Fig. 2. An individual with Klinefelter's syndrome. Note tall body proportions, gynecomastia, relative paucity of facial and body...
Functional Gonadotropin Deficiency
Men with chronic renal failure have reduced circulating total and free testosterone concentrations, unchanged sex hormone-binding globulin SHBG and elevated immunoreactive LH, FSH, and inhibin-a however, these changes are largely reversed after successful transplantation 1 . Although this pattern is consistent with a primarily defect in testicular function, there is also strong evidence for defective neuroendocrine regulation as an important functional aspect of the reproductive dysfunction in...
Use Of Recombinant Human Growth Hormone To Stimulate Spermatogenesis
Various direct or indirect effects of growth hormone GH and other growth factors on the process of sexual maturation have been postulated because deprivation of GH during maturation leads to impaired or absent spermatogenesis in male rats 53 . Furthermore, GH and growth factors, such as insulin-like growth factor-1 IGF-1 , epidermal growth factor EGF , and transforming growth factor TGF , influence testicular steroid production and secretion 54-56 . In mice, the testicular steroidogenic...
References Phf
1. Talbott E, Guzick D, Clerici A, et al. Coronary heart disease risk factors in women with polycystic ovary syndrome. Arterioscler Thromb Vasc Biol 1995 15 821-826. 2. Andersson B, Marin P, Lissner L, Vermeulen A, Bjorntorp P. Testosterone concentrations in women and men with NIDDM. Diabetes Care 1994 17 405-411. 3. Dunn JF, Nisula BC, Rodbard D. Transport of steroid hormones binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human...
References Msj
1. Lincoln GA, Short RV. Seasonal breeding nature's contraceptive. Rec Progr Horm Res 1980 36 1-52. 2. Lincoln GA, Rhind SM, Pompolo S, Clarke IJ. Hypothalamic control of photoepriod-induced cycles in food intake, body weight and metabolic hormones in rams. Am J Physiol Reg Integr Comp Physiol 2001 281 R76-R90. 3. Sharpe RM, Franks S. Environment, lifestyle and human infertility an inter-generational issue. Nature Med Cell Biol 2002 14 suppl 1 s33-s40. 4. Toppari J, Larsen JC, Christiansen P,...
Hormonal Regulation Of Spermatogenesis
The central role of the pituitary to stimulate spermatogenesis5 in adult primates was established nearly 60 yr ago 5 . Surgical removal of the pituitary gland in rhesus 5 In the context of this discussion, spermatogenesis is defined as the production of testicular spermatozoa whether one or many. Fig. 2. A schematic representation of the two mechanisms of stem cell renewal in higher primates. The top two diagrams illustrate the scheme that is common to rhesus monkey Macaca mulatta , African...
Endocrine Aspects Of Testicular Descent
A role for hormones in testicular descent was demonstrated more than 70 yr ago when a urinary extract from pregnant monkeys containing hCG was used to treat monkeys with cryptorchidism 54 . It remains unclear whether that was a direct gonadotropin effect or an indirect effect from increased testosterone production. The factors controlling testicular descent are clearly more complicated than hormone insufficiency alone, because only a portion of hypogonadotropic patients with Kallmann syndrome...
Hormone Production Sexual Development and Activity Hormone Production
Testosterone levels are generally normal in men with cryptorchidism, even those who were not treated 73,130 . Although testosterone levels are within the normal range in men who were formerly cryptorchid see Fig. 3 without other problems, a Fig. 4. Testosterone levels ng dL in men who were formerly cryptorchid plotted against age of orchidopexy. These data suggest lower levels in men with orchiopexy at older ages 1 . Fig. 4. Testosterone levels ng dL in men who were formerly cryptorchid plotted...
GnRH SYNTHESIS AND SECRETION
GnRH is the proximate regulator of reproduction. GnRH, a C-terminal amidated decapeptide is found in a small number of neurons that are located diffusely throughout the anterior hypothalamus in primates 1 . GnRH neurons send axons through subventricular and periventricular pathways to terminate in the capillary space within the median eminence. GnRH from these axons enters the capillaries and is transported in the hypothalamic portal blood to the cells of the anterior pituitary. Many factors...
Diagnostics
The physical examination reveals only a small proportion of all testicular tumors in CAH, depending on their size. For more accurate detection of these tumors, imaging techniques, such as ultrasound and magnetic resonance imaging MRI , are required 3,5,6,9,17,18 . A comparative study in males with CAH concluded that ultrasound is the method of choice, because it is as sensitive as MRI and more accessible 19 . Reports of ultrasound features show a similar picture of hypoechoic lesions adjacent...
Spermatogonia and Mitosis
Spermatogonia of mammals are always found adjacent to the basement membrane of the seminiferous tubule and are classified as either stem cells or differentiated sper-matogonia 19-26 . The first category, stem cells, are called type A spermatogonia, whereas differentiated spermatogonia are designated as type B spermatogonia. Type A spermatogonia in primates are further divided into dark type A, or Ad, spermatogonia, and pale type A, or Ap, spermatogonia 17,19-26 . The Ap spermatogonia divide to...
Congenital Idiopathic Hypogonadotropic Hypogonadism CIHH Definition
CIHH is characterized by an isolated defect in GnRH secretion or function. Criteria for the diagnosis of CIHH include 1 decreased T levels in the hypogonadal range e.g., lt 3.5 nmol L , 2 low normal gonadotropin levels representing absent or reduced GnRH secretion, 3 otherwise normal hormonal testing of the anterior pituitary, 4 a normal ferritin level, and, 5 normal radiographic imaging of the hypothalamic-pitu-itary region. Familial CIHH was reported in 1944, in association with anosmia and...
Infertility
Cryptorchidism may be a prominent cause of male infertility. Although there are no truly accurate indicators of male infertility, this number has been inferred from the portion of infertile couples whose infertility is believed to result from a male factor. It is estimated that 13 to 14 of couples in which the female partner is less than 45 yr of age are infertile excluding those who are surgically sterile 143 . In US studies, it is not possible to estimate what portion of these cases result...
Hormonal Treatment
Human chorionic gonadotropin hCG and gonadotropin-releasing hormone GnRH are being used in patients with cryptorchidism for both diagnostic and therapeutic purposes. No uniform regimen for hCG is superior for either purpose, and it is likely that most regimens provide maximal stimulation. Treatment for 3 to 4 d is practical and provides a reliable assessment of testicular responsiveness 119 . The use of the diagnostic test is limited to the situation in which neither testis is palpated. In the...
Hypotheses on Control of the Onset of Puberty
In 1931, Hohlweg presented a so-called gonadostat theory of puberty, which was based on the concept of a changing sensitivity of the gonadotropin-regulating system to the negative feedback effect of gonadal steroids 20 . This theory was further developed by Grumbach and colleagues 21 . Hohlweg and Junkmann observed that Fig. 3. The gonadostat hypothesis for puberty, i.e., a developmental change in the sensitivity of the gonadotropin-releasing hormone GnRH system in the regulation of...
Chronic Effects of LH
LH also has long-term trophic effects on Leydig cells, requiring both transcription and increased translation of proteins. Chronic stimulation by LH is required for maintenance of Leydig cell steroidogenic enzyme levels and to support the steroidogenic organelle aparatus, including mitochondrial membrane potential and SER volume. Inhibition of LH action can be achieved by hypophysectomy 91-93 , suppression of gonadotropins through steroid administration 94-96 , and neutralization of LH or...
OccupationalLifestyle Effects on Scrotal Temperature
Another situation in which occupational effects on male reproductive function might become apparent is if the occupational effect applies to a large proportion of men. It is possible that scrotal heating may be one such example. Scrotal, and therefore testicular, temperature has to be maintained some 3-4 C lower than core body temperature if normal spermatogenesis is to occur see Fig. 2 , and interference with the normal scrotal cooling process can profoundly affect sperm production, quality,...
Kinetics Of Spermatogenesis And Cycle Of The Seminiferous Epithelium
The kinetics of spermatogenesis are the temporal relationships among the various germ cells within the seminiferous epithelium as they proceed through mitosis, meiosis, and spermiogenesis 13,16,17,20,21 . The Sertoli cells, the only somatic cells found in the seminiferous epithelium, provide nourishment, growth factors, and organization to the germ cells 14 . These somatic cells span the entire seminiferous epithelium, sitting on the basement membrane and stretching to the lumen of the...
Diagnosis Mdg
These diseases are characterized by extensive damage to pituitary function. Therefore, hypogonadism is rarely reported as an isolated manifestation but, instead, is frequently associated with hypopituarism and diabetes insipidus. In addition, headache, vomiting, ophthalmoplegia, and visual loss occur with acute onset in pituitary apoplexy or head trauma and occur progressively in the empty sella syndrome, infectious and inflammatory processes, mucocele, arachnoid cyst, giant cell granuloma, and...
Factors Affecting Circulating Testosterone HypothalamicPituitaryTesticular Axis
Testosterone production at by the testis is under control of the hypothalamic-pituitary unit 22 . The operation and components of this axis are discussed in detail elsewhere in this volume see Chapters 1-3 and are not repeated here. The hypothalamic-pituitary-testicular axis hormones addressed in this discussion are luteinizing hormone LH , follicle-stimulating hormone FSH , inhibin, and prolactin PRL . Testosterone is freely diffusible through tissues, and, thus, its secretion from the testis...
Management Of Delayed Puberty
For induction of puberty in boys with constitutional delay of puberty, the indication for treatment is usually psychosocial boys with delayed puberty may suffer because of short stature and lack of pubertal progression. This distress may affect their school performance and their social relationships. Testosterone esters, given intramuscularly, remain the most commonly used treatment approach therapy can be started with 50 mg of a mixture of testosterone propionate and testosterone enanthate...
Measures Of Subclinical Atherosclerosis
Research in the field of atherosclerosis and cardiovascular disease has changed substantially in recent years because of the development of noninvasive methods of measuring the extent of atherosclerosis, including ultrasound measures of carotid intima-media wall thickness, CT measures of coronary artery and aortic calcification, ankle-brachial blood pressure assessments of lower extremity peripheral arterial disease, and measures of vascular stiffness, compliance, and pulse characteristics and...
Leydig Cell Tumors
Testicular tumors occur at a rate of 2 cases per 100,000 men and constitute 1 of all tumors in men. Leydig cell tumors LCTs account for 1 to 3 of testicular tumors 119 . LCTs were first identified by Sacchi in 1895 120 . Although they are rare gonadal stromal tumors, LCTs may occur at any age and represent approx 40 of all non-germ cell testicular tumors 121 . Most LCTs are unilateral only 3 are bilateral 121 . LCTs are found at all ages from 2 to 90 yr, with a peak occurrence in the fifth...
The Overtraining Syndrome
Several researchers have suggested that reproductive hormones in exercise-hypogo-nadal men are suppressed because they are overtraining, or are developing the overtraining syndrome. This terminology can be confusing to non exercise physiology researchers hence, some explanation is warranted. The terms overtraining syndrome and overtraining frequently are used interchangeably. The term overtraining refers to the process of heavier-than-usual exercise training, whereas the term overtraining...