madman
Super Moderator
The use of hormone stimulation in male infertility (2023)
Daniel Foran, Runzhi Chen, Channa N. Jayasena, Suks Minhas and Tharu Tharakan
Abstract
Infertility affects 15% of couples worldwide and in approximately 50% of cases, the cause is secondary to an abnormality of the sperm. However, treatment options for male infertility are limited and empirical use of hormone stimulation has been utilized. We review the contemporary data regarding the application of hormone stimulation to treat male infertility. There is strong evidence supporting the use of hormone stimulation in hypogonadotropic hypogonadism but there is inadequate evidence for all other indications.
Introduction
Infertility is the inability of a couple to achieve a spontaneous clinical pregnancy despite one year of regular, unprotected, sexual intercourse [1]. Infertility affects 15% of couples worldwide [2,3]. Of these cases, 20-50% are secondary to a male factor [4]. Male factor infertility is defined as the abnormality of semen analysis according to the World Health Organisation guidelines for semen parameters (Table 1) [1,5]. The etiology of male factor infertility can be categorized by the anatomical level of the abnormality (Figure 1) [6]. Up to 40% of cases are idiopathic [6].
Male infertility is on the rise and there is data showing a deterioration of sperm quality from 1982 to 2022 [7-10]. Male infertility has become the leading cause for Vitro fertilization (IVF) in the UK [11]. It is unclear why male infertility is increasing but rising levels of obesity and endocrine disruptors have been implicated [12-14]. Male infertility has also been associated with poorer general [15] and psychological health and holds a societal stigma associated with domestic violence [16].
Treatment options for male infertility are limited to assisted reproductive technologies (ARTs), namely in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Both ICSI and IVF success rates in male infertility are similar and align with the global average of 35% [17-19]. Moreover, each cycle of ART has been estimated to cost an average £3348 [20]. Healthcare resource management in the UK has resulted in restrictions on eligibility and funding for ART cycles [21,22].
The most severe manifestation of male infertility is azoospermia, the absence of sperm in the ejaculate. Azoospermia has been estimated to affect 1% of men, and 10-20% of males presenting to infertility clinics [23]. Azoospermia is classified as obstructive (OA) if there is a blockage to the conduit of the sperm or nonobstructive (NOA) when the is an impairment of sperm production. NOA accounts for 85-90% of azoospermia cases [6]. Whilst OA is commonly treatable with surgical correction or ICSI, NOA patients require surgical testicular sperm extraction (TESE). However, both TESE and microdissection TESE (mTESE) have success rates ranging from 30 to 64% [24]. Within this context hormone stimulation therapy has been trialed to improve sperm retrieval rates (SRRs).
The majority of the literature focuses on Azoospermia. Therefore, this narrative review will describe the contemporary data regarding the use of HST to treat NOA male infertility.
The rationale for hormone stimulation therapy
Spermatogenesis is the process by which germ cells differentiate into mature spermatozoa [25-27]. Sertoli cells control the hormonal milieu in the seminiferous tubules via follicle-stimulating hormone (FSH) and nourish and protect germ cells throughout spermatogenesis [28,29]. Luteinizing hormone (LH) stimulates Leydig cells to synthesize and release intratesticular testosterone (ITT) which is needed for the maturation of sperm (Spermiogenesis) [30-32].
Male hypogonadotropic hypogonadism is testicular failure secondary to gonadotropin deficiency. The rationale for HST in hypogonadotropic hypogonadism is that either replacement of the missing hormones (gonadotropin-releasing hormone (GnRH) or gonadotropins) or suppression of prolactin (an inhibitory hormone) will restore the hypothalamic-pituitary-gonadal (HPG) axis. Hypogonadotropic hypogonadism represents 1.9% of azoospermia cases and 1.6% of male infertility overall [33,34].
Hypergonadotropic Hypogonadism is intrinsic testicular failure associated with gonadotropin excess. Primary testicular failure represents 75% of all male factor infertility [35]. Eugonadism describes completely normal physiological hormone levels compatible with fertility. There are several theories behind the rationale for HST in hypergonadotropic and eugonadal patients.
It has been postulated that in hypergonadotropic hypogonadism the FSH receptor has become desensitized due to chronic high circulating gonadotropin levels and that hormone manipulation either with a GNRH antagonist followed by gonadotropin or through other HST may reset the HPG axis and restore spermatogenesis [36-41]. Furthermore, animal and human case reports have described a testosterone-independent pathway for spermatogenesis through supraphysiological HST-induced FSH stimulation [42-45]. It has been shown that ITT correlates poorly with serum testosterone (sT) [24,46-48] and therefore HST may be rationalized in eugonadism through overactivation of the HPG axis resulting in increased ITT production.
Types of hormone stimulation therapy
There have been several pharmacological therapies used to treat male infertility (Figure 2).
Gonadotropin-releasing hormone
GnRH is released by the hypothalamus and stimulates pituitary gonadotropin release. In patients with GnRH deficiency, such as Kallman’s syndrome, therapeutic GnRH stimulates pituitary gonadotropin secretion which subsequently induces ITT production and spermatogenesis. GnRH is mainly useful in congenital hypogonadotropic hypogonadism (CHH), excluding cases of GnRH receptor defects [49]. GnRH only exerts physiological effects when delivered in pulses [49]. Therefore, GnRH is delivered via a portable, subcutaneous pump, which administers GnRH boluses every 2 h for 12-24 months [49,50]. Doses vary from 25 to 600 ng/kg/bolus and are guided by hormonal response [49,50].
Gonadotropins
Gonadotropin therapy replicates the physiological function of LH and FSH in stimulating spermatogenesis and exists in several different formulations. Human chorionic gonadotropin (hCG) imitates LH, recombinant FSH (rFSH) imitates FSH, and human menopausal gonadotropin (hMG) contains a 1:1 ratio of LH:FSH. Gonadotropins are administered as subcutaneous injections. The typical dose of hCG ranges from 500 to 2500 International units (IU) given 2-3 times a week [49]. The typical doses of hMG or rFSH range from 75 to 225 IU given 2-3 times a week [49,51].
Selective estrogen receptor modulators
Selective estrogen Receptor Modulators (SERMs) act on estrogen receptors (ERs), in a tissue-specific manner, either as agonists or antagonists to alter the response to estrogen [52,53]. SERMs inhibit ERs in the hypothalamus and pituitary and suppress estrogen-mediated negative feedback on the HPG axis [52,53]. This upregulates gonadotropin and testosterone production. Tamoxifen Citrate (TC) and Clomiphene Citrate (CC) are the most commonly used SERMs. The typical doses of TC and CC range from 20 to 80 mg and 50-100 mg respectively, given once daily [51].
Aromatase inhibitors
Aromatase Inhibitors (AIs) inhibit the aromatase-mediated conversion of testosterone to estradiol within Leydig cells [54]. This increases peripheral circulating testosterone levels and decreases peripheral circulating estrogen levels [55]. The diminished estrogen levels reduce estrogen-mediated negative feedback on the HPG axis, upregulate gonadotropin production and consequently increase ITT production and spermatogenesis [55]. The common AIs include Anastrozole, Letrozole, and Testolactone. The typical doses of Anastrozole, Letrozole, and Testolactone are 1 mg, 2.5 mg, and 50-100 mg respectively, given once daily [51].
Dopamine agonists
Dopamine Agonists (DAs) activate dopamine receptors to induce the inhibition of prolactin secretion and the reduction of pituitary adenoma size [56]. By removing prolactin’s inhibitory effect on the pituitary and hypothalamic hormone secretion, DAs reactivate the HPG axis [57]. DAs are, therefore, used almost exclusively for hypogonadotropic hypogonadism secondary to prolactin-secreting pituitary adenomas [57]. The commonly used DAs include Cabergoline and Bromocriptine. The typical doses of Cabergoline and Bromocriptine range from 0.5 to 4.5 mg weekly and 1-30 mg daily respectively [58].
*For the purposes of this review, we will describe the use of HST in hypogonadotropic hypogonadism, hypergonadotropic hypogonadism, and eugonadism.
*Hormone stimulation in hypogonadotropic hypogonadism
*Hormone stimulation in hypergonadotropic hypogonadism (Table 2)
*Hormone stimulation in eugonadism (Table 2)
*Hormone stimulation in mixed cohorts
Conclusion
There is an urgent need to optimize SRRs and the management of male infertility. However, the literature supporting the use of HST is limited by a lack of high-level evidence, particularly RCTs. There is a theoretical plausibility supporting the use of HST in hypogonadotropic hypogonadism and this is reflected in the literature, which is largely supportive of the role of gonadotropins in restoring spermatogenesis. However, there is conflicting data regarding the use of HST in infertile men with hypergonadotropic hypogonadism and eugonadism. A recent meta-analysis demonstrated that HST may improve SSR in eugonadism but not hypergonadotropic hypogonadism, but the evidence level was poor, and the authors recommended the use of HST only in a clinical trial setting until more RCTs are performed [51].
The European Association of Urology and the Endocrine society both state that gonadotropins should be considered the standard treatment for men with hypogonadotropic hypogonadism who desire fertility but that they do not recommend any HST for induction of fertility in primary testicular failure [6,280]. Contemporary literature also lacks objective measures of fertility including PRs and LBRs. This is important because there needs to be a greater understanding regarding whether HST can change clinical outcomes. Furthermore, there needs to be an objective measure of all the potential adverse outcomes of HST. There is some data showing that HST can cause loss of libido, loss of hair, and cutaneous rashes all reported exclusively with AI use and acne associated with gonadotropin use. There are also reports of venous thromboembolism (VTE) in patients with Klinefelter’s Syndrome on HST [281-283]. Within the context of these adverse events, HST can only be recommended for male infertility secondary to hypogonadotropic hypogonadism, and further RCTs assessing PRs, LBRs, and drug safety profiles are needed.
Daniel Foran, Runzhi Chen, Channa N. Jayasena, Suks Minhas and Tharu Tharakan
Abstract
Infertility affects 15% of couples worldwide and in approximately 50% of cases, the cause is secondary to an abnormality of the sperm. However, treatment options for male infertility are limited and empirical use of hormone stimulation has been utilized. We review the contemporary data regarding the application of hormone stimulation to treat male infertility. There is strong evidence supporting the use of hormone stimulation in hypogonadotropic hypogonadism but there is inadequate evidence for all other indications.
Introduction
Infertility is the inability of a couple to achieve a spontaneous clinical pregnancy despite one year of regular, unprotected, sexual intercourse [1]. Infertility affects 15% of couples worldwide [2,3]. Of these cases, 20-50% are secondary to a male factor [4]. Male factor infertility is defined as the abnormality of semen analysis according to the World Health Organisation guidelines for semen parameters (Table 1) [1,5]. The etiology of male factor infertility can be categorized by the anatomical level of the abnormality (Figure 1) [6]. Up to 40% of cases are idiopathic [6].
Male infertility is on the rise and there is data showing a deterioration of sperm quality from 1982 to 2022 [7-10]. Male infertility has become the leading cause for Vitro fertilization (IVF) in the UK [11]. It is unclear why male infertility is increasing but rising levels of obesity and endocrine disruptors have been implicated [12-14]. Male infertility has also been associated with poorer general [15] and psychological health and holds a societal stigma associated with domestic violence [16].
Treatment options for male infertility are limited to assisted reproductive technologies (ARTs), namely in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Both ICSI and IVF success rates in male infertility are similar and align with the global average of 35% [17-19]. Moreover, each cycle of ART has been estimated to cost an average £3348 [20]. Healthcare resource management in the UK has resulted in restrictions on eligibility and funding for ART cycles [21,22].
The most severe manifestation of male infertility is azoospermia, the absence of sperm in the ejaculate. Azoospermia has been estimated to affect 1% of men, and 10-20% of males presenting to infertility clinics [23]. Azoospermia is classified as obstructive (OA) if there is a blockage to the conduit of the sperm or nonobstructive (NOA) when the is an impairment of sperm production. NOA accounts for 85-90% of azoospermia cases [6]. Whilst OA is commonly treatable with surgical correction or ICSI, NOA patients require surgical testicular sperm extraction (TESE). However, both TESE and microdissection TESE (mTESE) have success rates ranging from 30 to 64% [24]. Within this context hormone stimulation therapy has been trialed to improve sperm retrieval rates (SRRs).
The majority of the literature focuses on Azoospermia. Therefore, this narrative review will describe the contemporary data regarding the use of HST to treat NOA male infertility.
The rationale for hormone stimulation therapy
Spermatogenesis is the process by which germ cells differentiate into mature spermatozoa [25-27]. Sertoli cells control the hormonal milieu in the seminiferous tubules via follicle-stimulating hormone (FSH) and nourish and protect germ cells throughout spermatogenesis [28,29]. Luteinizing hormone (LH) stimulates Leydig cells to synthesize and release intratesticular testosterone (ITT) which is needed for the maturation of sperm (Spermiogenesis) [30-32].
Male hypogonadotropic hypogonadism is testicular failure secondary to gonadotropin deficiency. The rationale for HST in hypogonadotropic hypogonadism is that either replacement of the missing hormones (gonadotropin-releasing hormone (GnRH) or gonadotropins) or suppression of prolactin (an inhibitory hormone) will restore the hypothalamic-pituitary-gonadal (HPG) axis. Hypogonadotropic hypogonadism represents 1.9% of azoospermia cases and 1.6% of male infertility overall [33,34].
Hypergonadotropic Hypogonadism is intrinsic testicular failure associated with gonadotropin excess. Primary testicular failure represents 75% of all male factor infertility [35]. Eugonadism describes completely normal physiological hormone levels compatible with fertility. There are several theories behind the rationale for HST in hypergonadotropic and eugonadal patients.
It has been postulated that in hypergonadotropic hypogonadism the FSH receptor has become desensitized due to chronic high circulating gonadotropin levels and that hormone manipulation either with a GNRH antagonist followed by gonadotropin or through other HST may reset the HPG axis and restore spermatogenesis [36-41]. Furthermore, animal and human case reports have described a testosterone-independent pathway for spermatogenesis through supraphysiological HST-induced FSH stimulation [42-45]. It has been shown that ITT correlates poorly with serum testosterone (sT) [24,46-48] and therefore HST may be rationalized in eugonadism through overactivation of the HPG axis resulting in increased ITT production.
Types of hormone stimulation therapy
There have been several pharmacological therapies used to treat male infertility (Figure 2).
Gonadotropin-releasing hormone
GnRH is released by the hypothalamus and stimulates pituitary gonadotropin release. In patients with GnRH deficiency, such as Kallman’s syndrome, therapeutic GnRH stimulates pituitary gonadotropin secretion which subsequently induces ITT production and spermatogenesis. GnRH is mainly useful in congenital hypogonadotropic hypogonadism (CHH), excluding cases of GnRH receptor defects [49]. GnRH only exerts physiological effects when delivered in pulses [49]. Therefore, GnRH is delivered via a portable, subcutaneous pump, which administers GnRH boluses every 2 h for 12-24 months [49,50]. Doses vary from 25 to 600 ng/kg/bolus and are guided by hormonal response [49,50].
Gonadotropins
Gonadotropin therapy replicates the physiological function of LH and FSH in stimulating spermatogenesis and exists in several different formulations. Human chorionic gonadotropin (hCG) imitates LH, recombinant FSH (rFSH) imitates FSH, and human menopausal gonadotropin (hMG) contains a 1:1 ratio of LH:FSH. Gonadotropins are administered as subcutaneous injections. The typical dose of hCG ranges from 500 to 2500 International units (IU) given 2-3 times a week [49]. The typical doses of hMG or rFSH range from 75 to 225 IU given 2-3 times a week [49,51].
Selective estrogen receptor modulators
Selective estrogen Receptor Modulators (SERMs) act on estrogen receptors (ERs), in a tissue-specific manner, either as agonists or antagonists to alter the response to estrogen [52,53]. SERMs inhibit ERs in the hypothalamus and pituitary and suppress estrogen-mediated negative feedback on the HPG axis [52,53]. This upregulates gonadotropin and testosterone production. Tamoxifen Citrate (TC) and Clomiphene Citrate (CC) are the most commonly used SERMs. The typical doses of TC and CC range from 20 to 80 mg and 50-100 mg respectively, given once daily [51].
Aromatase inhibitors
Aromatase Inhibitors (AIs) inhibit the aromatase-mediated conversion of testosterone to estradiol within Leydig cells [54]. This increases peripheral circulating testosterone levels and decreases peripheral circulating estrogen levels [55]. The diminished estrogen levels reduce estrogen-mediated negative feedback on the HPG axis, upregulate gonadotropin production and consequently increase ITT production and spermatogenesis [55]. The common AIs include Anastrozole, Letrozole, and Testolactone. The typical doses of Anastrozole, Letrozole, and Testolactone are 1 mg, 2.5 mg, and 50-100 mg respectively, given once daily [51].
Dopamine agonists
Dopamine Agonists (DAs) activate dopamine receptors to induce the inhibition of prolactin secretion and the reduction of pituitary adenoma size [56]. By removing prolactin’s inhibitory effect on the pituitary and hypothalamic hormone secretion, DAs reactivate the HPG axis [57]. DAs are, therefore, used almost exclusively for hypogonadotropic hypogonadism secondary to prolactin-secreting pituitary adenomas [57]. The commonly used DAs include Cabergoline and Bromocriptine. The typical doses of Cabergoline and Bromocriptine range from 0.5 to 4.5 mg weekly and 1-30 mg daily respectively [58].
*For the purposes of this review, we will describe the use of HST in hypogonadotropic hypogonadism, hypergonadotropic hypogonadism, and eugonadism.
*Hormone stimulation in hypogonadotropic hypogonadism
*Hormone stimulation in hypergonadotropic hypogonadism (Table 2)
*Hormone stimulation in eugonadism (Table 2)
*Hormone stimulation in mixed cohorts
Conclusion
There is an urgent need to optimize SRRs and the management of male infertility. However, the literature supporting the use of HST is limited by a lack of high-level evidence, particularly RCTs. There is a theoretical plausibility supporting the use of HST in hypogonadotropic hypogonadism and this is reflected in the literature, which is largely supportive of the role of gonadotropins in restoring spermatogenesis. However, there is conflicting data regarding the use of HST in infertile men with hypergonadotropic hypogonadism and eugonadism. A recent meta-analysis demonstrated that HST may improve SSR in eugonadism but not hypergonadotropic hypogonadism, but the evidence level was poor, and the authors recommended the use of HST only in a clinical trial setting until more RCTs are performed [51].
The European Association of Urology and the Endocrine society both state that gonadotropins should be considered the standard treatment for men with hypogonadotropic hypogonadism who desire fertility but that they do not recommend any HST for induction of fertility in primary testicular failure [6,280]. Contemporary literature also lacks objective measures of fertility including PRs and LBRs. This is important because there needs to be a greater understanding regarding whether HST can change clinical outcomes. Furthermore, there needs to be an objective measure of all the potential adverse outcomes of HST. There is some data showing that HST can cause loss of libido, loss of hair, and cutaneous rashes all reported exclusively with AI use and acne associated with gonadotropin use. There are also reports of venous thromboembolism (VTE) in patients with Klinefelter’s Syndrome on HST [281-283]. Within the context of these adverse events, HST can only be recommended for male infertility secondary to hypogonadotropic hypogonadism, and further RCTs assessing PRs, LBRs, and drug safety profiles are needed.
