Restoring spermatogenesis in hypogonadotrophic hypogonadism

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madman

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Hypogonadism is a deficiency in one of the testes’ two major functions: (a) testosterone secretion (endocrine function) and (b) spermatogenesis (reproductive function). The two types are known as primary (hypergonadotrophic) hypogonadism (testis failure) and secondary (hypogonadotrophic) hypogonadism, and are disorders of the hypothalamic−pituitary axis.


When low testosterone levels and/or defective sperm analysis are combined with high serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, the primary type is diagnosed. Low or inadequate gonadotrophin levels describe the secondary type, which is the polar opposite.

Testosterone replacement therapy is the most effective treatment for males with hypogonadism. Androgens are necessary for virilization and appropriate sexual function, for the maintenance of muscle and bone mass, and for normal mood and cognition. Even though testosterone is the first-line treatment for restoring secondary sexual characteristics and sexual performance, testosterone replacement therapy does not restore fertility in men with hypogonadism.

Primary and secondary hypogonadism need different strategies for achieving pregnancy in people who want to be fathers. Patients should be referred to assisted reproductive technology (ART) procedures, such as surgical testicular sperm extraction and in vitro intracytoplasmic sperm injection (ICSI) in the former.

In the latter, exogenous gonadotrophins, which are widely available, or pulsatile gonadotrophin-releasing hormone (GnRH) can be used to promote spermatogenesis. FSH in the form of human menopausal gonadotrophins (hMG), highly purified urinary FSH preparations, or recombinant FSH formulations are used in traditional therapy.
The findings suggest that normal qualitative and quantitative sperm production is best maintained in the presence of both FSH- and LH-induced testosterone secretion. Human chorionic gonadotrophin (hCG) in conjunction with FSH is a common regimen for inducing spermatogenesis. Given their structural similarity (functioning through the same receptor on Leydig cells), purified hCG is an efficient alternative for LH.

In some countries, a range of FSH formulations is currently accessible. FSH has traditionally been given in the form of hMG, obtained from postmenopausal women’s urine. Although hMG has both FSH and LH activity, FSH activity predominates, and LH activity is so low that fertility requires a combination of hCG and hMG. More recently, highly pure urinary FSH preparations have been created, with higher specific activity than hMG. Recombinant human FSH formulations have greater purity and specific activity than any urinary preparation and no inherent LH activity.


Typically, hCG alone at a dose of 1000IU on alternate days or twice weekly is usually used to start gonadotrophin therapy, with the dose titrated based on trough testosterone levels and testicular development. Alternatively, prefilled syringes of recombinant hCG can be used for subcutaneous injection. As testicular size grows in certain patients, the hCG dose can be reduced over time. Due to residual FSH secretion, spermatogenesis can be begun with hCG alone in most individuals with bigger testes at baseline.

Once there is a plateau in the response to hCG, which typically occurs at around 6 months, therapy with FSH (in one of the three forms described above) should be added at a dose of 75IU on 3 days per week. If sperm output and testicular growth remain suboptimal, the dose of FSH can be gradually increased to 150IU daily.

Gynaecomastia is the most prevalent side effect of gonadotrophin therapy and is caused by increased oestradiol release due to hCG activation of aromatase. This unfavorable side effect can be avoided by taking the smallest dose of hCG that keeps serum testosterone levels at the lower end of the normal range.


Sperm density remains below normal in most individuals with hypogonadotrophic hypogonadism treated with gonadotrophins. Clinicians should be aware that, while 75% of men will generate sperm, long-term therapy rarely results in counts returning to normal. Failure to acquire a normal sperm density, on the other hand, does not rule out fertility. Indeed, spermatozoa have a high quality and fertilizing capacity, resulting in spontaneous conception even when sperm quantity is low.

Several determinants of fertility outcome have been identified in hypogonadotrophic hypogonadism. Cryptorchidism suggests a bad outlook for fertility, and in men with hypogonadotrophic hypogonadism generally necessitates long-term treatment (18–24 months). Low serum levels of inhibin B and/ or prepubertal testicular volume <4ml are also negative indicators of reproductive outcome.

A sequential treatment for the most severely affected males with hypogonadotrophic hypogonadism (testicular volume <4ml) has emerged, in an attempt to enhance reproductive potential. Before maturation by hCG, unopposed FSH increases the growth of immature Sertoli and germ cells. This regimen successfully induces testicular development and fertility in men with congenital hypogonadotrophic hypogonadism who have prepubertal testes.


If a pregnancy is achieved, treatment could be continued during the first trimester, to maintain male fertility in the case of a miscarriage. If the couple decides to try for a second pregnancy shortly, hCG therapy can be resumed. On the other hand, following a live birth, patients with hypogonadotrophic hypogonadism should be switched to testosterone replacement medication (injectable or transdermal formulations) for long-term treatment.

Pulsatile administration of GnRH, which can be via a programmable, portable mini-infusion pump, provides an alternative to gonadotrophin therapy. FSH–hCG therapy provides two advantages over GnRH therapy: subcutaneous delivery and greater efficacy in cases of GnRH receptor mutation (about 10% of normosmic congenital hypogonadotrophic hypogonadism). Furthermore, due to a lack of randomized research, pulsatile GnRH treatment is not licensed by US Food and Drug Administration for induction of spermatogenesis, and its usage is thus limited to specialist clinics.



Settimio D’Andrea
Italy




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madman

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Male germinal epithelium, showing Sertoli cells (yellow), spermatogonia (pink), primary spermatocytes in pachytene phase (blue), spermatids (green), spermatozoa (red), residual bodies (light blue)
 

madman

Super Moderator
*The findings suggest that normal qualitative and quantitative sperm production is best maintained in the presence of both FSH- and LH-induced testosterone secretion. Human chorionic gonadotrophin (hCG) in conjunction with FSH is a common regimen for inducing spermatogenesis

*Although hMG has both FSH and LH activity, FSH activity predominates, and LH activity is so low that fertility requires a combination of hCG and hMG

*More recently, highly pure urinary FSH preparations have been created, with higher specific activity than hMG. Recombinant human FSH formulations have greater purity and specific activity than any urinary preparation and no inherent LH activity

*Typically, hCG alone at a dose of 1000IU on alternate days or twice weekly is usually used to start gonadotrophin therapy, with the dose titrated based on trough testosterone levels and testicular development

*Due to residual FSH secretion, spermatogenesis can be begun with hCG alone in most individuals with bigger testes at baseline

*Once there is a plateau in the response to hCG, which typically occurs at around 6 months, therapy with FSH (in one of the three forms described above) should be added at a dose of 75IU on 3 days per week. If sperm output and testicular growth remain suboptimal, the dose of FSH can be gradually increased to 150IU daily

*Gynaecomastia is the most prevalent side effect of gonadotrophin therapy and is caused by increased oestradiol release due to hCG activation of aromatase

*Pulsatile administration of GnRH, which can be via a programmable, portable mini-infusion pump, provides an alternative to gonadotrophin therapy. FSH–hCG therapy provides two advantages over GnRH therapy: subcutaneous delivery and greater efficacy in cases of GnRH receptor mutation (about 10% of normosmic congenital hypogonadotrophic hypogonadism)
 
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