madman
Super Moderator
Abstract
Introduction: Testosterone (T) replacement therapy causes suppression of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) that can lead to a decrease in semen parameters and possible infertility. Different T formulations may have varying suppression on FSH and LH.
Objective: To study whether shorter-acting T (multiple daily dosing) has less suppression on FSH and LH serum levels compared with longer-acting T (transdermal gel, injectable).
Methods: A systematic literature search was conducted by following the protocol based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis protocols. We comprehensively reviewed the literature by systematically searching manuscripts indexed in PubMed from 1995 to March 13, 2019, to identify studies reporting changes in FSH and LH in hypogonadal men treated with exogenous T which evaluated the effect of exogenous T on FSH and LH.
Results: A total of 8 studies reported the effect of T on FSH and LH in 793 hypogonadal men: 2 used long-acting injectables (enanthate or undecanoate) in a total of 16 men, 5 used intermediate-acting daily topical gels or patches in a total of 471 men, and 1 used short-acting intranasal T (125mL/nostril, twice a day or three times a day) in 306 men. Long-acting injectables decreased FSH by 86.3%, intermediate-acting daily gels/patches decreased FSH by 60.2%, and short-acting intranasal gel decreased FSH by 37.8%. Long-acting injectables decreased LH by 71.8%, intermediate-acting daily gels/patches decreased LH by 59.2%, and short-acting intranasal gel decreased LH by 47.3%.
Conclusions: Our findings suggest that short-acting T preparations do not decrease serum FSH or LH to the same extent as longer-acting transdermal gels and injectables. However, further clinical trial data are necessary to determine whether the effect of short-acting TRT on gonadotropins translates into similar changes in semen parameters and fertility.
INTRODUCTION
Low testosterone (low T) affects 35% of men older than the age of 45 years.1Treatment generally consists of T replacement therapy (TRT) using exogenous forms of T: long-lasting pellets, injections, transdermal gels and patches, and intranasal gel. 2 Direct-to-consumer marketing has increased awareness of low T leading to an increased number of prescriptions for TRT. 3 What is concerning is that about 12% of TRT prescriptions are prescribed to men of reproductive age. 4 Some of the side effects of TRT is decreased intratesticular T levels, infertility, azoospermia, and testicular atrophy 2- all of which can be detrimental to men of reproductive age. In fact, up to 65% of normal men become azoospermic after 6 months of TRT (weekly intramuscular injections of 200 mg T enanthate) and testis volume can decrease by 23%. 5,6 Current strategies for increasing T without affecting fertility or testis volume are off-label prescriptions of estrogen receptor modulators (eg, clomiphene citrate), aromatase inhibitors (eg, anastrozole), and human chorionic gonadotropin. 2 The main reason that human chorionic gonadotropin and clomiphene citrate is able to preserve spermatogenesis is thought to be because of preservation of intratesticular T. Previous studies showed the utility of 17-hydroxyprogesterone as a biomarker of intratesticular T and demonstrated that 17-hydroxyprogesterone was undetectable in men receiving exogenous T, in contrast to those in the control group (men with serum T≤300 mg/dL not receiving any treatment) and men treated with human chorionic gonadotropin and/or clomiphene citrate (P<.05). 7 Because these medications are off label for the symptomatic treatment of hypogonadal men, and most not Food and Drug Administration approved for use in men, identifying strategies to increase T that may lessen side effects are critical.
Azoospermia and testicular atrophy result from exogenous T suppression of the hypothalamic-pituitary-gonadal axis via a negative feedback mechanism. In our prior work, a short-acting nasal gel T (Natesto, Food, and Drug Administration approved, May 2014) was shown to increase serum T, maintain gonadotropins luteinizing hormone (LH), and follicle-stimulating hormone (FSH), within the normal range, and not significantly affect semen parameters. 8 Unlike the dosing of other forms of exogenous T (subdermal pellets, injections, and trans-dermal gels) that provide steady delivery for 24 hours or more, the nasal gel is delivered either 2 or 3 times a day, providing discrete peaks (or pulses) in serum T levels with a return to baseline T levels between peaks. Pulsatile dosing, and more importantly, the existence of daily troughs between doses, may allow for reinitialization of the pulsatile release of gonadotropin-releasing hormone (GnRH) and therefore maintaining the production of LH and FSH. Because GnRH release cannot be directly measured in humans, FSH and LH are used as surrogates.9 We, therefore, hypothesized that short-acting T has a lesser effect on serum levels of gonadotropins (LH and FSH) than long-acting exogenous T.
Discussion
The secretion of gonadotropins, LH and FSH, is stimulated by GnRH release from the hypothalamus onto the pituitary.18 The mechanism of how 1 hormone, GnRH, can stimulate the release of 2 distinct gonadotropins can be explained by the frequency of its release. When GnRH is released in fast pulses, approximately every 1-2 hours, the pituitary favors the release of LH and stimulates the production of T from the testicle. In contrast, for FSH secretion, the pituitary needs to receive a pulse of GnRH every4-6 hours. 19, 20 In our study, we saw the suppression of both LH and FSH with all forms of T; however, the suppression was less pronounced with short-acting T. 17 Interestingly, less suppression of FSH compared with that of LH was noted in the short-acting T (Table 2). Although serum GnRH is unable to be measured, LH has been used as an indirect measure of GnRH secretion. This preservation of LH in the serum with short-acting T formulations suggests that the shorter-acting T formulations may have less suppression on the hypothalamic-pituitary-gonadal axis and GnRH pulsatility.
The gonadotropins FSH and LH stimulate testicular function. The physiological role of LH is the stimulation of T synthesis from Leydig cells. FSH stimulates Sertoli cells that support spermatogonial differentiation and maturation and the production of androgen-binding proteins that are essential in maintaining the high intratesticular T levels. 21 More than 95% of the testicular volume is dedicated to spermatogenesis, and without LH and FSH, the synthetic functions of the testes come to a halt, leading to atrophy and infertility. Therefore, short-acting T, through maintenance of LH and FSH release, may preserve testicular function, including spermatogenesis and endogenous T production; however, prospective studies evaluating the effects of short-acting T are needed.
CONCLUSION
Our analyses support that long-acting Ts may have greater suppression of FSH and LH than shorter-acting formulations. However, further clinical trial data are necessary to determine whether the effect of short-acting TRT on gonadotropins translates into differences in side effects, such as fertility and testis volume.
Introduction: Testosterone (T) replacement therapy causes suppression of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) that can lead to a decrease in semen parameters and possible infertility. Different T formulations may have varying suppression on FSH and LH.
Objective: To study whether shorter-acting T (multiple daily dosing) has less suppression on FSH and LH serum levels compared with longer-acting T (transdermal gel, injectable).
Methods: A systematic literature search was conducted by following the protocol based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis protocols. We comprehensively reviewed the literature by systematically searching manuscripts indexed in PubMed from 1995 to March 13, 2019, to identify studies reporting changes in FSH and LH in hypogonadal men treated with exogenous T which evaluated the effect of exogenous T on FSH and LH.
Results: A total of 8 studies reported the effect of T on FSH and LH in 793 hypogonadal men: 2 used long-acting injectables (enanthate or undecanoate) in a total of 16 men, 5 used intermediate-acting daily topical gels or patches in a total of 471 men, and 1 used short-acting intranasal T (125mL/nostril, twice a day or three times a day) in 306 men. Long-acting injectables decreased FSH by 86.3%, intermediate-acting daily gels/patches decreased FSH by 60.2%, and short-acting intranasal gel decreased FSH by 37.8%. Long-acting injectables decreased LH by 71.8%, intermediate-acting daily gels/patches decreased LH by 59.2%, and short-acting intranasal gel decreased LH by 47.3%.
Conclusions: Our findings suggest that short-acting T preparations do not decrease serum FSH or LH to the same extent as longer-acting transdermal gels and injectables. However, further clinical trial data are necessary to determine whether the effect of short-acting TRT on gonadotropins translates into similar changes in semen parameters and fertility.
INTRODUCTION
Low testosterone (low T) affects 35% of men older than the age of 45 years.1Treatment generally consists of T replacement therapy (TRT) using exogenous forms of T: long-lasting pellets, injections, transdermal gels and patches, and intranasal gel. 2 Direct-to-consumer marketing has increased awareness of low T leading to an increased number of prescriptions for TRT. 3 What is concerning is that about 12% of TRT prescriptions are prescribed to men of reproductive age. 4 Some of the side effects of TRT is decreased intratesticular T levels, infertility, azoospermia, and testicular atrophy 2- all of which can be detrimental to men of reproductive age. In fact, up to 65% of normal men become azoospermic after 6 months of TRT (weekly intramuscular injections of 200 mg T enanthate) and testis volume can decrease by 23%. 5,6 Current strategies for increasing T without affecting fertility or testis volume are off-label prescriptions of estrogen receptor modulators (eg, clomiphene citrate), aromatase inhibitors (eg, anastrozole), and human chorionic gonadotropin. 2 The main reason that human chorionic gonadotropin and clomiphene citrate is able to preserve spermatogenesis is thought to be because of preservation of intratesticular T. Previous studies showed the utility of 17-hydroxyprogesterone as a biomarker of intratesticular T and demonstrated that 17-hydroxyprogesterone was undetectable in men receiving exogenous T, in contrast to those in the control group (men with serum T≤300 mg/dL not receiving any treatment) and men treated with human chorionic gonadotropin and/or clomiphene citrate (P<.05). 7 Because these medications are off label for the symptomatic treatment of hypogonadal men, and most not Food and Drug Administration approved for use in men, identifying strategies to increase T that may lessen side effects are critical.
Azoospermia and testicular atrophy result from exogenous T suppression of the hypothalamic-pituitary-gonadal axis via a negative feedback mechanism. In our prior work, a short-acting nasal gel T (Natesto, Food, and Drug Administration approved, May 2014) was shown to increase serum T, maintain gonadotropins luteinizing hormone (LH), and follicle-stimulating hormone (FSH), within the normal range, and not significantly affect semen parameters. 8 Unlike the dosing of other forms of exogenous T (subdermal pellets, injections, and trans-dermal gels) that provide steady delivery for 24 hours or more, the nasal gel is delivered either 2 or 3 times a day, providing discrete peaks (or pulses) in serum T levels with a return to baseline T levels between peaks. Pulsatile dosing, and more importantly, the existence of daily troughs between doses, may allow for reinitialization of the pulsatile release of gonadotropin-releasing hormone (GnRH) and therefore maintaining the production of LH and FSH. Because GnRH release cannot be directly measured in humans, FSH and LH are used as surrogates.9 We, therefore, hypothesized that short-acting T has a lesser effect on serum levels of gonadotropins (LH and FSH) than long-acting exogenous T.
Discussion
The secretion of gonadotropins, LH and FSH, is stimulated by GnRH release from the hypothalamus onto the pituitary.18 The mechanism of how 1 hormone, GnRH, can stimulate the release of 2 distinct gonadotropins can be explained by the frequency of its release. When GnRH is released in fast pulses, approximately every 1-2 hours, the pituitary favors the release of LH and stimulates the production of T from the testicle. In contrast, for FSH secretion, the pituitary needs to receive a pulse of GnRH every4-6 hours. 19, 20 In our study, we saw the suppression of both LH and FSH with all forms of T; however, the suppression was less pronounced with short-acting T. 17 Interestingly, less suppression of FSH compared with that of LH was noted in the short-acting T (Table 2). Although serum GnRH is unable to be measured, LH has been used as an indirect measure of GnRH secretion. This preservation of LH in the serum with short-acting T formulations suggests that the shorter-acting T formulations may have less suppression on the hypothalamic-pituitary-gonadal axis and GnRH pulsatility.
The gonadotropins FSH and LH stimulate testicular function. The physiological role of LH is the stimulation of T synthesis from Leydig cells. FSH stimulates Sertoli cells that support spermatogonial differentiation and maturation and the production of androgen-binding proteins that are essential in maintaining the high intratesticular T levels. 21 More than 95% of the testicular volume is dedicated to spermatogenesis, and without LH and FSH, the synthetic functions of the testes come to a halt, leading to atrophy and infertility. Therefore, short-acting T, through maintenance of LH and FSH release, may preserve testicular function, including spermatogenesis and endogenous T production; however, prospective studies evaluating the effects of short-acting T are needed.
CONCLUSION
Our analyses support that long-acting Ts may have greater suppression of FSH and LH than shorter-acting formulations. However, further clinical trial data are necessary to determine whether the effect of short-acting TRT on gonadotropins translates into differences in side effects, such as fertility and testis volume.
Last edited:
