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Klinefelter syndrome, 47,XXY KS , is the most frequent sex chromosome aberration in males, affecting 1 in newborn boys. The syndrome is characterized by testicular destruction with extensive fibrosis and hyalinization of the seminiferous tubules resulting in small testes, hypergonadotropic hypogonadism, and azoospermia in the majority of cases.
Until recently, infertility was considered an untreatable condition in KS. However, with the development of new advanced assisted reproductive techniques such as testicular sperm extraction TESE combined with ICSI it seems that KS patients should no longer be labelled as infertile. Especially, microdissection micro -TESE has proved to be an advantageous procedure for the identification of testicular spermatozoa in KS.
The aim of this review was to describe current knowledge on the testicular changes occurring in KS, the associated changes in reproductive hormones and spermatogenesis, and the existing possibilities of biological fatherhood in 47,XXY patients. Klinefelter syndrome, 47,XXY KS , is characterized by a progressive testicular failure causing small firm testes, androgen deficiency, and azoospermia 1.
The syndrome is generally diagnosed at three main stages in life: The presence of a sex chromosome aneuploidy affects the patient at multiple organ levels. Although many individuals with sex chromosome variations can live functionally normal lives, others may experience physical, developmental, psychosocial, behavioural, and learning disabilities.
The natural history of these clinical findings is not completely elucidated. Some may be a consequence of the hypogonadism typical for this syndrome, whereas others may be directly related to the chromosome abnormality. Although the vast majority of men with nonmosaic KS are azoospermic, motile sperms in the ejaculate and even spontaneous pregnancies resulting from KS fathers have been described, although such cases are rare 6 , 7 , 8 , 9 , Thus, in the majority of cases use of donor semen or more rarely by adoption has been the only possible way of becoming a father.
In successful recovery of spermatozoa by TESE in men with azoospermia and KS was reported for the first time 12 , with the first pregnancies reported in In the present review we describe current knowledge on the testicular changes occurring in KS, the associated changes in reproductive hormones and spermatogenesis, and the existing possibilities of biological fatherhood in 47,XXY patients.
Infertility in KS is a consequence of germ cell degeneration that commences already in utero , progresses slowly during infancy and early childhood, and accelerates during puberty and adolescence, eventually resulting in extensive fibrosis and hyalinization of the seminiferous tubules and hyperplasia of interstitium in the adult patient for review see Testicular volume is significantly reduced in infants and prepubertal boys with KS as compared with similarly aged healthy boys 15 , 16 , indicating that the number of seminiferous tubules is significantly reduced before puberty.
As illustrated in Figs 1 and 2 , germ cell degeneration is already noted in the pubertal Klinefelter boy. Accordingly, Wikstrom et al. In addition, Wikstrom et al. It has been shown that azoospermic Klinefelter men may have single residual foci with preserved spermatogenesis 4 , 19 , 20 , 21 , 22 , 23 , 24 , 25 and may benefit from assisted reproductive techniques to father a child. Histological sections from testicular biopsies from boys of various ages with normal testicular function left panel and from boys with nonmosaic Klinefelter syndrome right panel.
From fetal life until puberty the testicular architecture seems similar except that the number of germ cells is markedly reduced in the sample from the prepubertal Klinefelter boy. During and after puberty gross morphological changes with widespread degeneration and hyalinization of the seminiferous tubules in the Klinefelter subject are noted. In the adult most of the biopsy consists of clumps of Leydig cells. Clinical and biological parameters in boys, adolescents and adults with nonmosaic Klinefelter syndrome: Acta Paediatrica —, with permission.
Testicular biopsies from patients with KS at various ages. A Fourteen-year-old boy with complete hyalinization of seminiferous tubules. C Eighteen-year-old male with heterogeneous, adult-type pattern with tubules with spermatogenesis left , and a few Sertoli cell-only tubules right mixed with completely hyalinized tubules and Leydig cell hyperplasia.
D Nineteen-year-old male with heterogeneous adult-type pattern with differentiated Sertoli cells, type A left and incompletely differentiated Sertoli cells type B right , fibrosis and Leydig cell hyperplasia. E Twenty-five-year-old male presenting with heterogeneous adult pattern showing type A top and type B middle Sertoli cells.
F Twenty-nine-year-old male with adult pattern showing large Leydig cell clumps, a few Sertoli cell-only tubules, and ghost tubules marked with L.
G Thirty-year-old male with adult pattern. Note the tubules with spermatogenesis embedded in large Leydig cell clumps denoted by L. Adult pattern with impaired spermatogenesis embedded in Leydig cells and hyalinized tubules arrows. Adult pattern with scattered Sertoli cell-only tubules marked with S embedded in large Leydig cell clumps. In infancy, around the age of 3 months, the hypothalamic—pituitary—gonadal HPG axis is transiently activated in the so-called mini-puberty 26 , 27 , 28 , The initial activation of the HPG axis is believed to be important for genital development, including renewal and differentiation of the germ cells Dysfunction of any of the components of the mini-puberty may underlie the lowered eventual sperm counts in boys with hypogonadotropic hypogonadism by decreasing the number of spermatogonia produced for the future The mini-puberty represents a window suitable for studying the function of the pituitary—gonadal axis at this young age by measuring the spontaneous, basal hormone levels Although controversies exist as to whether the HPG axis is impaired in KS infants 16 , 33 , 34 , 35 , the latest and largest study on the mini-puberty in KS demonstrated normal testosterone concentrations Importantly, however, the testosterone concentrations were below the median of the controls, which may indicate a subtle Leydig cell dysfunction, although this was not supported by an elevation of LH concentrations This could most likely reflect the fact that androgen receptors are not highly expressed at 3 months and that the normal feedback system is not functioning.
KS boys usually enter puberty at the expected age with an initial normal increase in testicular volume Fig. However, from around midpuberty the testicular deterioration occurs, as evidenced by a regression of testicular volume 5 , 41 Fig. Concomitantly, a dramatic decline is observed in inhibin B concentrations, which are most often undetectable at the end of puberty in Klinefelter patients 17 , 38 , The physiological pubertal decline in serum AMH is also observed in KS, although this occurs later than observed in healthy boys 18 , 43 , At midpuberty, a relative hypogonadism is usually evident by increasing LH and FSH concentrations to hypergonadotropic levels.
FSH increases earlier and more markedly than LH 5 , 36 , 37 , The serum concentration of testosterone is most often in the lower half of the reference range of healthy males, and rarely below the reference range. Inhibin B is below the detection limit in the vast majority of KS adults reflecting the absent spermatogenesis 39 , whereas the circulating concentrations of AMH and INSL3 are significantly reduced compared with healthy males 40 , 45 , Mean testes volume in KS adults is 3.
Longitudinal measures of testicular volume by palpation in 79 untreated nonmosaic KS patients. Repeated measures in the same patient are connected by a blue line. Mean testes volume in adults is indicated by the black line in the right side of the figure modified from 5.
Cryopreservation of spermatozoa is currently offered to boys undergoing gonadotoxic treatments, which may render them sterile. The success rate of obtaining sperm from masturbation in adolescent boys depends on the degree of pubertal maturation, but also psychological factors influence whether or not it is possible to obtain a semen sample by masturbation. In the few KS patients where motile sperms are seen in the ejaculate, cryopreservation should be offered 6.
Anecdotally, it has been proposed that the chance of finding motile sperm in the ejaculate would be higher in semen samples from early pubertal KS boys before the destruction of the seminiferous tubules has been completed. However, we were not successful in 12 out 12 KS adolescents aged 15—20 years 6. In contrast, Lanfranco et al. Ejaculated semen from men with KS has been used for ICSI and to date at least eight live born children have been reported 48 , 49 , 50 , 51 , During recent years, cryopreservation of spermatogonial stem cells SSCs has been offered on an experimental basis to immature boys prior to chemo- or radiotherapy with the purpose of being hypothetically able to reintroduce the SSCs in the patient's own testis by SSC transplantation.
So far, in vitro spermatogenesis of human SSCs has not been possible, but this technique might become an option in the future since the in vitro differentiation of mouse SSCs up to mature sperm cells has recently been reported 53 , Since KS testes are characterized by extensive fibrosis and hyalinization of the seminiferous tubules, the ultimate use of the SSCs is likely to differ from that of boys with a normal karyotype.
At present, cryopreservation with or without preceding TESE must be considered an experimental approach in adolescents with KS. Thus, it may be interesting as part of a research protocol, but it clearly remains to be seen if this will become a standard offer to such boys. Until recently, the only way to become a father for males with KS was by the use of donor insemination or adoption.
Conventional TESE is based on multiple blind testis biopsies, whereas micro-TESE is based on microsurgery to identify individual seminiferous tubules with active spermatogenesis.
The micro-TESE technique has proved superior to TESE with respect to minimizing the damage to the testicular tissue, and maximizing the success rate of sperm retrieval A total of 14 mosaics were included in these studies 56 , Exclusion of these did not change the success rates. Early androgen replacement therapy in the peripubertal period is generally recommended to allow for normal pubertal development and age-appropriate attainment of muscle and bone mass, although no randomized controlled trial evaluating the effect of this approach exists at present.
In patients already receiving androgen replacement therapy, it has been suggested to discontinue this treatment for at least 6 months prior to micro-TESE Alternative therapeutic options with aromatase inhibitor testolactam or anastrozol , human chorionic gonadotropin hCG , or clomiphene are often applied, but no controlled trials exist.
Uncontrolled studies have reported moderate positive effects on sperm retrieval rates in patients with nonobstructive azoospermia NOA 78 , However, controversy exists and a very recent study on men with NOA found that neither baseline testosterone nor the response to preoperation hormonal therapy had any effect on overall sperm retrieval, clinical pregnancy, or live birth rates In fact, even patients with inhibin B below the detection limit underwent successful TESE in one study Likewise, we reported two KS subjects with motile spermatozoa in their ejaculate one of the patients fathered a child spontaneously ; both had undetectable inhibin B and highly elevated FSH levels, and could not be distinguished from KS patients with persistent azoospermia 6.
This is in accordance with the concept of a progressive degradation of the spermatogonia, and based on single case reports, declining spermatogenesis with ageing in Klinefelter men has been reported 9 , In addition, one study found a positive predictive value of testicular volume, testosterone levels and response to hCG test for successful TESE 62 , but this association was not confirmed in others 66 , 70 , Furthermore, no association between outcome of TESE and testicular ultrasonography, intratesticular blood-flow resistance, or degree of virilization has been found 66 , 70 , In the study by Ramasamy et al.
However, the existing results are contradicting and no single parameter has been identified so far. Similar results have been reported in studies on patients with nonmosaic KS. Similar results have been published by Ishikawa et al. They concluded that the decline in serum testosterone may be related to the small testicular volume and Leydig cell loss near the scars after the procedures. With the increasing chances for KS males of fathering children by the use of assisted reproductive techniques, the chromosomal condition of the germ cells in the testis from KS patients is both of scientific and practical medical interest.
Investigations of the ejaculated or testicular spermatozoa in KS with the fluorescent in-situ hybridization technique have shown varying frequencies of normal spermatozoa ranging from Accordingly, it has been proposed that adults with KS have a substantially higher proportion of hyperhaploid spermatozoa 46,XY and 46,XX than healthy males 93 , 94 , giving these males a theoretically increased risk of fathering a child with 47,XXY or 47,XXX for review see Furthermore, an increased frequency of autosomal aneuploidy 13, 18, and 21 in spermatozoa from KS has been proposed 52 , 93 , Importantly, Blanco et al.
Despite a substantial evidence that only diploid, XY, germ cells can turn into meiosis in the XXY mice 98 , and that XXY germ cells are absent in the testes of adult XXY mice 99 , this subject remains controversial in humans 4 , 97 , , , However, in two recent studies of nonmosaic KS patients all meiotic spermatocytes were normally euploid and thus able to mature into haploid spermatozoa 25 , This technique allows for selecting chromosomally abnormal embryos in order to avoid transferring abnormal embryos.
Analyzing the autosomes separately, the difference was only significant for chromosomes 18 and 21 with both monosomies 18 and 21 and trisomies 18 and 21 present. In conclusion, low—normal testosterone and elevated LH serum concentrations are typical findings in KS and merit androgen supplementation in a majority of patients.
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Many translated example sentences containing "ejaculate semen" – German- English dictionary and search production is also controlled by testosterone. Released in the blood, testosterone will increase physical manifestations of virility (muscle mass, energy, etc.) as well as acting on the libido and on sperm. All steroids measured in blood and semen were similarly affected and all of plasma levels of dehydroepiandrosterone sulphate and testosterone in the boar.