Clomiphene to Natesto results

[madman]

Converting men from Clomiphene Citrate to Natesto for hypogonadism improves libido, maintains semen parameters, and reduces estradiol
Parviz K. Kavoussi M.D., G. Luke Machen M.D., Melissa S. Gilkey M.S., Shu-Hung Chen M.S., Keikhosrow M. Kavoussi M.D., Amy Esqueda R.N.C., M.S.N., A.P.R.N., J. David Wininger P.h.D., Maya Barsky M.D., M.S.C.I., Shahryar K. Kavoussi M.D., M.P.H.


Abstract:

Objective: To evaluate outcomes including libido, semen parameters, testosterone, estradiol (E2), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) when converting men with low libido on Clomiphene Citrate (CC) to Natesto.

Methods: A retrospective chart review was performed. Baseline hormones prior to treatment, and again on CC and Natesto, as well as semen parameters on CC and on Natesto, were assessed.

Results: In forty-one men, there was no difference in serum testosterone levels on CC versus Natesto, however; there was a significantly higher E2 on CC than on Natesto. Although FSH levels were significantly lower on Natesto than at baseline, the mean FSH level on Natesto remained in the normal reference range. There was no difference in LH levels at baseline versus on Natesto. There was not a significant difference in semen parameter values when men were on CC versus when they were on Natesto for 3 months. At 3 months after changing to Natesto, 38/41 (92.7%) men reported significantly improved libido on Natesto when compared to CC.

Conclusions: Men on CC and Natesto reach eugonadal testosterone levels, however; on CC the E2 level nearly doubled from baseline and converting men from CC to Natesto returned E2 3 to nearly baseline levels. There was not a detrimental effect on semen parameters, and there was subjective reporting of improved libido after converting from CC to Natesto in this cohort, but further long-term studies are needed prior to Natesto being established as a definitive treatment for hypogonadism for men desiring to maintain fertility.


Introduction

There has been a rise in the prevalence of low testosterone in adolescents and young adults, for whom current or future fertility potential may be important.1,2 Long-acting traditional testosterone replacement therapy (TRT) modalities, such as transdermal gels and intramuscular injections, suppress the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH), thereby suppressing spermatogenesis downstream by decreasing intratesticular testosterone levels. 3-5 Clomiphene Citrate (CC) is a selective estrogen receptor modulator, which is an off-label treatment for men with hypogonadism in a spermatogenic preserving manner. The mechanism of action of CC is inhibition of estradiol negative feedback to the hypothalamus resulting in increased secretion of LH stimulating Leydig cells of the testes to produce testosterone. 6 Most men have normalization of testosterone levels on CC to eugonadal levels, but estradiol (E2) levels commonly rise, and symptomatic response on CC has been reported to be less optimal than on TRT, particularly libido. 7 The 4.5% intranasal TRT, Natesto, is administered at a fairly low dose of 11 mg per dose administration and is administered at more frequent intervals of twice or three times daily, which allow FSH and LH to remain in normal reference range levels. A clinical trial by Ramasamy et al revealed that men treated with Natesto did not have significant suppression of semen parameter values from baseline. 8 The objective of the current study was to evaluate the impact of converting men who suffered from low libido on CC to Natesto and assessing the effect on serum testosterone levels, FSH, LH, E2, and semen analysis parameter values, as well as libido.


Conclusions

Although men reached eugonadal testosterone levels on both CC and Natesto, men on CC nearly doubled their E2 levels from baseline, and converting men from CC to Natesto returned E2 to nearly baseline levels. In this patient cohort, there was not a detrimental effect on semen parameters, and there was subjective reporting of improved libido after converting from CC to Natesto, however; there is a need for longer-term studies beyond six months of treatment prior to concluding that Natesto is an appropriate treatment for hypogonadal men desiring to maintain fertility.

 

[Nelson Vergel]

More on Natesto

 

[madman]

Table 1. Baseline Demographics. Age and BMI expressed in means ± stand deviation.

 

[madman]

Table 2. Hormonal parameters at baseline, on Clomiphene Citrate, and on Natesto for men with hypogonadism (n = 41). Semen parameters on Clomiphene Citrate and on Natesto. Results are expressed as means ± standard deviations. P values for testosterone and estradiol levels are comparing men on Clomiphene Citrate vs Natesto. P values for follicle-stimulating hormone and luteinizing hormone levels are comparing baseline levels to men treated with Natesto.

 

[madman]

Discussion

Hypogonadism is a common diagnosis in men presenting with a constellation of symptoms prompting an evaluation to initiate treatment. Testosterone levels may start to decline in men at 30 years of age. Once this decline in testosterone levels begins, there may be a decrease by 1-2% per year. 10 However, the prevalence of low testosterone in younger men is increasing, which complicates the treatment options. 1,2 Classically, TRT has been the treatment of choice for hypogonadism, however; other long-acting TRT modalities suppress the hypothalamic-pituitary-gonadal (HPG) axis and thereby, downstream spermatogenesis, and result in testicular atrophy due to the diminishment of spermatogenesis. 11 This makes TRT a poor choice for hypogonadal men trying to achieve a pregnancy or for those wanting to maintain fertility potential. 3,4 To avoid suppression of the HPG axis and spermatogenesis, CC is commonly prescribed off-label to increase serum testosterone levels in a manner that does not suppress spermatogenesis, and long-term studies on safety and efficacy on CC have been published.6 However, men on CC have demonstrated high rates of hyperestrogenemia necessitating co-administration of aromatase inhibitors. This is seen commonly in clinical practice and has been published in multiple studies. 6,12-14 CC can have other undesirable side effects such as gynecomastia, weight gain, and fatigue.12

The cohort in this current study showed similar improvements in serum testosterone levels to eugonadal levels as previously published studies on CC. 12,13,15-18 However, the concerns with the use of CC in this population of men include the common complaint of low libido on CC as well as the frequently reported rise in E2 levels. Dadhich et al published a study revealing that men on CC have a less robust symptomatic response, especially with libido, in comparison to men on direct TRT. 7 This is a common clinical complaint in practice when treating men with CC. The long-standing challenge has been a treatment for hypogonadal men desiring to maintain fertility potential which could increase serum testosterone levels to eugonadal levels, not increase estradiol significantly, and offer the symptomatic response, particularly with libido, that TRT offers.

The current study suggests that Natesto is an alternative treatment for hypogonadal men desiring to maintain fertility potential in a manner that optimizes libido response and minimizes aromatization of testosterone to E2. In comparison to other forms of TRT, the more frequent and short-acting formulation of Natesto mimics the physiologic testosterone release which is the hypothesis for the potential to maintain gonadotropins and spermatogenesis. 8,19,20 It has been described that diurnal variation of serum testosterone levels and modalities of TRT with a short half-life, such as Natesto, more closely duplicate physiology.21,22 In the current study, the lower levels of normal for FSH and LH in the reference laboratory were 1.5 IU/L and 1.2 IU/L respectively. While on Natesto, seven men (17%) had an FSH level of below 1.5 IU/L, only one of which suppressed below 1.0 IU/L, none of which became undetectably low. Only one of the men had LH suppress below 1.2 IU/L (2%). In that man, the LH was 1.0 IU/L. Although some men did suppress gonadotropins below the laboratory reference range cutoff for low, the majority did not, and of those who did, the gonadotropins remained detectable. Having less profound LH suppression likely accounts for the maintenance of spermatogenesis even in these men, by allowing for intratesticular testosterone.

 

[TLawyer]

Discussion

Hypogonadism is a common diagnosis in men presenting with a constellation of symptoms prompting an evaluation to initiate treatment. Testosterone levels may start to decline in men at 30 years of age. Once this decline in testosterone levels begins, there may be a decrease by 1-2% per year. 10 However, the prevalence of low testosterone in younger men is increasing, which complicates the treatment options. 1,2 Classically, TRT has been the treatment of choice for hypogonadism, however; other long-acting TRT modalities suppress the hypothalamic-pituitary-gonadal (HPG) axis and thereby, downstream spermatogenesis, and result in testicular atrophy due to the diminishment of spermatogenesis. 11 This makes TRT a poor choice for hypogonadal men trying to achieve a pregnancy or for those wanting to maintain fertility potential. 3,4 To avoid suppression of the HPG axis and spermatogenesis, CC is commonly prescribed off-label to increase serum testosterone levels in a manner that does not suppress spermatogenesis, and long-term studies on safety and efficacy on CC have been published.6 However, men on CC have demonstrated high rates of hyperestrogenemia necessitating co-administration of aromatase inhibitors. This is seen commonly in clinical practice and has been published in multiple studies. 6,12-14 CC can have other undesirable side effects such as gynecomastia, weight gain, and fatigue.12

The cohort in this current study showed similar improvements in serum testosterone levels to eugonadal levels as previously published studies on CC. 12,13,15-18 However, the concerns with the use of CC in this population of men include the common complaint of low libido on CC as well as the frequently reported rise in E2 levels. Dadhich et al published a study revealing that men on CC have a less robust symptomatic response, especially with libido, in comparison to men on direct TRT. 7 This is a common clinical complaint in practice when treating men with CC. The long-standing challenge has been a treatment for hypogonadal men desiring to maintain fertility potential which could increase serum testosterone levels to eugonadal levels, not increase estradiol significantly, and offer the symptomatic response, particularly with libido, that TRT offers.

The current study suggests that Natesto is an alternative treatment for hypogonadal men desiring to maintain fertility potential in a manner that optimizes libido response and minimizes aromatization of testosterone to E2. In comparison to other forms of TRT, the more frequent and short-acting formulation of Natesto mimics the physiologic testosterone release which is the hypothesis for the potential to maintain gonadotropins and spermatogenesis. 8,19,20 It has been described that diurnal variation of serum testosterone levels and modalities of TRT with a short half-life, such as Natesto, more closely duplicate physiology.21,22 In the current study, the lower levels of normal for FSH and LH in the reference laboratory were 1.5 IU/L and 1.2 IU/L respectively. While on Natesto, seven men (17%) had an FSH level of below 1.5 IU/L, only one of which suppressed below 1.0 IU/L, none of which became undetectably low. Only one of the men had LH suppress below 1.2 IU/L (2%). In that man, the LH was 1.0 IU/L. Although some men did suppress gonadotropins below the laboratory reference range cutoff for low, the majority did not, and of those who did, the gonadotropins remained detectable. Having less profound LH suppression likely accounts for the maintenance of spermatogenesis even in these men, by allowing for intratesticular testosterone.

Skimmed the actual report, but looks like 85% of the men on Natesto required only twice daily treatment to get these results?

 

[madman]

Skimmed the actual report, but looks like 85% of the men on Natesto required only twice daily treatment to get these results?

All men were initiated on Natesto 11 mg twice daily intranasal administration, and if they did not achieve eugonadal levels obtained 1 hour after administration of Natesto 1 month after initiation of treatment, the dose was titrated up to 3 times daily. Only 6/41 (14.6%) of the men required up-titration to three times daily dosing. The results reported on Natesto were on the treatment regimen that achieved eugonadal levels.

 

[TLawyer]

All men were initiated on Natesto 11 mg twice daily intranasal administration, and if they did not achieve eugonadal levels obtained 1 hour after administration of Natesto 1 month after initiation of treatment, the dose was titrated up to 3 times daily. Only 6/41 (14.6%) of the men required up-titration to three times daily dosing. The results reported on Natesto were on the treatment regimen that achieved eugonadal levels.

I would think that twice daily would be a lot more palatable than three times daily (which I think is the manufacturer's recommended frequency). I wonder if there is a decent percentage where only once daily would be sufficient.

 

[madman]

I would think that twice daily would be a lot more palatable than three times daily (which I think is the manufacturer's recommended frequency). I wonder if there is a decent percentage where only once daily would be sufficient.

For monotherapy, once-daily dosing would not suffice!

post #22

Anyone tried testosterone base (no ester)?

But is there something special about doing it three times with the nasal gel? Maybe in the the Natesto product development phase they experimented with different frequencies? Are there any references for the half-life of testosterone in oil? What if it is hours instead of minutes? If so then a...

www.excelmale.com

But is there something special about doing it three times with the nasal gel? Maybe in the Natesto product development phase, they experimented with different frequencies?

I think with multiple peaks (2-3x daily) it would more effective and you would reap the overall beneficial effects regarding (energy/mood/libido/erectile function/body composition).

They state that testosterone levels or symptoms are used to guide titration decisions between either twice daily or three times a day doses used to restore testosterone levels to the normal range.

If dosing once daily was truly optimal there would be no need for 2-3 times/day application


*Based on the data, Acerus believes that the mechanism of action of NATESTO® is unique whereby the peaks in testosterone generated by NATESTO® dosing provide efficacy and improvement of symptoms, while the time between doses (4-8 hours) allows for the maintenance of testicular testosterone production and sperm production.

*The 24-hour pharmacokinetic profile of testosterone for patients on TNG treatment has two or three discrete peaks (“pulses”) of testosterone provoked by LH secretions that occur on average every 2 hours. A maximal peak of testosterone appears at about 1h (Tmax) followed by a return to endogenous, pre-dose levels, 4-6 hours later (t1/2 ~1h).

*Natesto, a testosterone-based nasal gel, is self-administered three times per day. Approximately 40 minutes after administration, testosterone levels return to normal, although Natesto’s half-life is widely variable, between 10 and 100 minutes.

 

[Nelson Vergel]

I have no idea who likes to snort anything twice or three times per day. I can see it probably useful before the gym or sex LOL.

Natesto gave me sinus issues and I developed a pimple by one of my nostrils. It also gave me a headache every single time as T levels shoot right after administration. Not a fan.

 

[TLawyer]

I have no idea who likes to snort anything twice or three times per day. I can see it probably useful before the gym or sex LOL.

Natesto gave me sinus issues and I developed a pimple by one of my nostrils. It also gave me a headache every single time as T levels shoot right after administration. Not a fan.

I see on the Natesto directions not to blow or sniff your nose for an hour. So would that suggest that after an hour any medication/gel still in your nose doesn't have any impact on T levels? In other words, after you hit the peak after about an hour, you could completely remove everything left in your nose and it wouldn't matter on levels?