Nomogram to predict changes in semen parameters following clomiphene citrate therapy for males with abnormal semen parameters

Introduction

Close to 15% of couples will have subfertility, with a male factor contributing to the infertility approximately 50% of the time.¹ While there are often reversible factors identified to treat men with subfertility, empiric hormonal therapy has become a popular therapy used to treat men with idiopathic infertility.

Clomiphene citrate (CC) is the most commonly prescribed medication for idiopathic male infertility in the United States.^2,3 The use of CC for the management of ovulation predates the use for men, but there are reports dating back to the 1960s about CC use to treat infertile men with oligospermia.^4–6 CC is an antiestrogen blocking the feedback of estradiol on the hypothalamus/pituitary axis to increase the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH).^7,8 This in turn increases the local concentration of FSH and LH in the testis, reportedly increasing the production of testosterone and sperm.^7–9 In a meta-analysis published in 2013, Chua et al., reported that anti-estrogen use for men with infertility resulted in statistically significantly increased pregnancy rates with an OR of 2.42 (95% CI: 1.47–3.94), sperm counts with a weighted mean difference of 5.24 million/mL (CI: 2.12–8.37) and sperm motility of a weighted mean difference of 4.55% (CI: 0.73–8.37%).⁹ There was heterogeneity in the dose, type (either CC or tamoxifen) and duration of anti-estrogen analyzed for the meta-analysis.

CC is a relatively safe therapy with Guo et al., reporting from a US claims database no increased incidence of side effects in those using CC, although there was a report of an embolic event occurring with CC use.^2,10

From these previous reports, there is evidence that the use of CC leads to improvements in semen parameters and pregnancy rates, but the magnitude of the expected response for individual patients is unknown.

The expected magnitude of change in semen parameters is critical in deciding therapies for couples with infertility. Men with total motile sperm counts (TMC) < 5 million generally will be referred for in-vitro fertilization (IVF), while men with TMC > 5 million are candidates for intra-uterine insemination (IUI) and men with TMC > 9 million are candidates to try to conceive spontaneously.¹ The potential goals of therapies for men with infertility is not only to achieve a spontaneous pregnancy, but also to “upgrade” semen parameters so couples might be able to conceive with less invasive assisted reproductive technologies (ARTs) (moving from needing IVF to being candidates for IUI).

Our goal was to develop nomograms based on baseline semen, hormonal and patient characteristics to predict the semen and hormonal changes following CC use. This should allow patients and clinicians to predict the individual’s expected changes in semen parameters and hormone levels following CC treatment, in turn allowing clinicians to tailor the fertility therapies and provide specific information to men on their specific expected outcomes.

Methods

This prospective cohort study took place at the Murray Koffler Urologic Wellness Centre at Mount Sinai Hospital, Toronto, Canada and was approved by Mount Sinai Hospital Research Ethics Board with approval number 14-0342-E. All participants provided written informed consent for the use and publication of the patients’ data. Patients were enrolled in this study between 2016–2019 and followed up to 2019. Men attending a specialized male infertility clinic were assessed for fertility. Standardized baseline clinical information including demographic information, fertility history, medical/surgical history and medication use was obtained on all men and prospectively recorded. A description of the initial physical finding was recorded for all men (height, weight, testicular size, presence of varicocele by physical examination).

Results

Prediction of individual patient sperm concentration following three months of clomiphene citrate therapy

A model was developed (Figure 1) which predicted sperm concentration following three months of therapy with CC. Initial sperm concentration, LH, T, age and sperm motility were all independently predictive of the increase in sperm concentration following CC therapy (Table 1). These as well as serum FSH were included to provide a predicted sperm concentration for individual patients (Figure 1) and to provide the probability that the man’s sperm concentration will be > 15million/mL (WHO normal range), total motile count > 5 million/mL (range below which IVF is often recommended) and 0 million/mL (nomogram available at http://riskcalc.org/clomiphene_citrate/). Predictive probability of the model is shown in Figure 2.

Figure 1. Predicted sperm concentration following three months of clomiphene citrate therapy based on age, hormone values and initial semen parameters.

Figure 2. Predictive probability of the model for sperm concentration.

(ZINB: Zero inflated negative binomial modeling).

Predicted testosterone levels following three months of clomiphene citrate therapy

The post-CC testosterone levels were most closely and significantly correlated to the pre-CC testosterone levels (Table 3), but the addition of information on gonadotropin levels and age significantly improved the predictive performance of the model. The nomogram is shown in Figure 3 with the online nomogram available at (nomogram available at http://riskcalc.org/clomiphene_citrate/). Conversely, LH and FSH levels post-CC also correlated significantly to the pre-CC LH and FSH levels respectively and not significantly to other parameters (Tables 4–6).

Table 3. Model parameters for testosterone levels following three months of clomiphene citrate therapy.

Parameter	Estimate	s.e.	95% CI	p-value
Intercept	0.064	0.015	0.034,0.095	<0.01
Age_initial.form	0.000	0.000	0.000,0.001	0.19
T.Pre	-0.000	0.001	-0.006,-0.001	<0.01
FSH.Pre	0.001	0.000	0.000,0.001	0.06
Volume.Pre	0.002	0.001	0.000,0.004	0.07
SpermConc.Pre > 0	-0.003	0.006	-0.016,0.009	0.61

Figure 3. Nomogram to predict serum testosterone concentration following three months of clomiphene citrate therapy for men with infertility.

(FSH: follicle stimulating hormone).

Table 4. Model parameters for leutinizing hormone levels following three months of clomiphene citrate use.

Parameter	Estimate	s.e.	95% CI	p-value
Intercept	7.157	1.029	5.118, 9.196	<0.001
LH.Pre	0.243	0.070	0.103, 0.382	<0.001
FSH.Pre	0.126	0.049	0.029, 0.223	0.012
SpermConc.Pre > 0	-2.877	0.905	-4.669, -1.085	0.002

Table 5. Model parameters for FSH following three months of clomiphene citrate use.

Parameter	Estimate	s.e.	95% CI	p-value
Intercept	4.508	5.899	-7.177, 16.193	0.446
Age_initial.form	0.105	0.172	-0.236, 0.446	0.542
Age_initial.form’	-0.387	0.252	-0.885, 0.112	0.128
FSH.Pre	0.675	0.057	0.563, 0.787	<0.001
Motility.Pre>0	-0.716	1.374	-3.438, 2.006	0.603
SpermConc.Pre > 0	-2.852	1.672	-6.164, 0.460	0.091

Table 6. Model parameters for sperm motility following three months of clomiphene citrate use.

	Logit section				Negative binomial section
	Estimate	z value	p-value	95% CI for Estimate	Estimate	z value	p-value	95% CI for Estimate
(Intercept)	0.908	2.088	0.037	0.056, 1.76	3.011	5.092	0.000	1.852, 4.169
Motility.Pre	0.170	0.587	0.557	-0.398, 0.739	0.024	5.195	0.000	0.015, 0.033
Motility.Pre=0	-19.896	-1.214	0.225	-52.018, 12.227	-0.093	-0.325	0.745	-0.656, 0.469
Age_initial.form	-				-0.009	-0.809	0.419	-0.03, 0.012
T.Pre	-				0.006	0.567	0.571	-0.015, 0.027
Volume.Pre	-				0.045	1.127	0.260	-0.033, 0.124
SpermConc.Pre	-				0.001	0.462	0.644	-0.002, 0.004
SpermConc.Pre=0	-				-0.240	-0.537	0.591	-1.115, 0.635

Discussion and conclusion

CC is widely used as an empiric therapy to manage male infertility. Edmund Y. Ko et al., in 2012 reported that CC is the most widely prescribed medication among urologists in the American Urological Association for the treatment of idiopathic male infertility.³

While certainly there are studies which do not show any benefit of CC to treat male fertility, most notably a very large, controlled trial published in 1992,^15,16 the majority of studies do show improvements in sperm parameters and pregnancy rates with CC therapy^9,17,18 A meta-analysis by Chua et al., published in 2013 found a 2.4 OR (95% CI: 1.47–3.94) of pregnancy in couples where the men were taking empiric CC therapies.⁹

What remains unclear is the expected response to the CC for individual patients, information which would help couples decide on therapies and allow clinicians to tailor therapies to the individual patient.

With this present study, we have developed a nomogram (available at http://riskcalc.org/clomiphene_citrate/) using baseline values of age, FSH, LH, T levels and semen parameters (volume, count and motility) to provide the expected semen parameters and testosterone levels following CC therapy as well as the odds of having normal sperm counts and total motile counts of > 5 million sperm (level at which IUI could be considered).¹⁹ These are the first published nomograms on the expected changes in semen parameters and testosterone levels for individual men following clomiphene citrate therapy.

This nomogram will help clinicians predict the chances of clinically meaningful responses to CC therapy. As an example, a 36-year-old male with semen volume = 1.6 mL, sperm concentration = 7 million/mL and motility = 23% (sperm values where IVF might be recommended), FSH = 3, LH = 2 and T = 12, following CC therapy will have an expected semen volume = 1.6 mL, sperm concentration = 21 million/mL, sperm motility = 21%. There is a 46% chance that his sperm count will be > 15 million/ml (normal) and a 48% chance that the total motile count will be > 9 million. He would have a good chance to increase his sperm parameters to a level where a spontaneous pregnancy is possible.

As another example, a 34-year-old male with baseline semen volume = 1.3mL, sperm concentration = 3 million/mL and sperm motility = 20% (likely needing IVF) with FSH = 3.5, LH = 3 and T = 9. Following CC therapy, the expected semen volume = 1.3mL, sperm concentration = 8.6 million/mL, sperm motility = 20%. Following CC therapy, there is only a 7% chance that his sperm counts will be normal and a 4% chance that the total motile count would be > 9 million. Most likely, this couple would still need to manage the fertility with IVF even after the CC therapy. These are two examples of how this nomogram could help with treatment planning for couples with male factor infertility.

There are several limitations of this study: data comes from a single center using a single CC therapy protocol and should be replicated in other centers, the numbers of patients recruited with azoospermia (due to spermatogenic failure) is low, meaning that our nomogram is likely to be less accurate for men with spermatogenic failure and the men consumed “fertility” vitamins and minerals throughout this study. While guidelines from the American Urology Association and the American Society of Reproductive Medicine conclude that supplements are of “questionable clinical utility in treating male infertility” with non-significant effects on sperm counts, our study can’t preclude an effect of a combination of supplements and CC.²⁰

Paradoxically, the weakness of a single centre is also a strength, with one laboratory for all of the biological testing, which improves the consistency of the testing.

This is the first study to publish a predictive model for expected post therapy sperm parameters in men using CC. This is an important study since it provides clinicians with information to help personalize fertility care for the couples. This type of nomogram will allow clinicians to have a more informed discussion with patients about the expected semen parameters with CC “treatment” and allow couples to make a more informed decision to select between the many options that exist to treat and/or manage (using the Assisted Reproductive Technologies (ARTs)) male infertility.

Finally, in the future, a goal should be to develop personalized predicted pregnancy rates with the use of CC therapy. This would allow clinicians to directly compare the outcomes of CC therapy with the use of the ARTs.

Data availability

Consent

Written informed consent for publication of the patients’ details was obtained from the patients.