madman
Super Moderator
Medical therapy for male infertility : Current Opinion in Urology
trogen modulators, and aromatase inhibitors to either improve or restore spermatogenesis in men with hormonal abnormalities (e.g. hypogonadotropic/hypergonadotropic hypogonadism, hyperprolactinemia) or supraphysiologic levels (e.g. exogenous testosterone/anabolic steroid use). Despite the...
journals.lww.com
Purpose of review
To provide up-to-date evidence and clinical guidance on the role of medical therapy in the context of hormonal imbalances affecting human spermatogenesis.
Recent findings
Compelling evidence has accumulated over the years regarding the role of gonadotropins, selective estrogen modulators, and aromatase inhibitors to either improve or restore spermatogenesis in men with hormonal abnormalities (e.g. hypogonadotropic/hypergonadotropic hypogonadism, hyperprolactinemia) or supraphysiologic levels (e.g. exogenous testosterone/anabolic steroid use). Despite the increasing number of studies being performed, most of the available evidence relies on small nonrandomized studies, mainly in men with hypergonadotropic hypogonadism or with history of exogenous testosterone/anabolic steroid use. As such, the efficacy of medical therapy is highly variable emphasizing the necessity of randomized clinical trials and individualized approaches.
Summary
This narrative review provides clinical guidance on medical therapies for male factor infertility based on the most up-to-date evidence, focusing on treatments for hormonal abnormalities (either hypogonadotropic or hypergonadotropic hypogonadism and hyperprolactinemia) and supraphysiologic levels (and exogenous testosterone/anabolic steroid use) to improve spermatogenesis.
INTRODUCTION
Spermatogenesis is a complex physiological process that takes place in the seminiferous tubules of the testes during a man’s adult life [1–3]. This process is regulated by the hypothalamic–pituitary–gonadal(HPG) axis, which maintains the proper hormonal balance through negative and positive feedback loops, ensuring effective spermatogenesis [3,4]. The hypothalamus is responsible for activating the whole HPG axis by secreting gonadotropin releasing hormone (GnRH). GnRH stimulates the anterior pituitary gland to secrete two distinct gonadotropic hormones: luteinizing hormone and follicle-stimulating hormone (FSH) [2–4]. Luteinizing hormone stimulates the Leydig cells in the testicular interstitium to produce testosterone (T),which is essential for the growth and division of germinal cells, marking the beginning of sperm formation [3,5]. Conversely, FSH targets the Sertoli cells,which are crucial for spermiogenesis, the final stage of sperm development where spermatids mature into functional sperms [2–4]. The secretion of these hormones is tightly regulated by negative feedback mechanisms which involve two additional hormones: estradiol (E2) and inhibin B (InhB) [3,4,6,7].E2, derived from the peripheral conversion of T by the enzyme aromatase, reduces GnRH expression in the hypothalamus, which in turn regulates the production of gonadotropins (FSH and luteinizing hormone) [4,7]. InhB, produced by the Sertoli cells,specifically inhibits FSH secretion from the anterior pituitary, thus maintaining FSH levels within the optimal range for spermatogenesis [6]. As such,understanding the HPG axis is crucial for understanding the rationale of using specific medical therapies for male factor infertility (MFI) [8&,9]. In this regard,this narrative review aims to provide a detailed overview of current available medical treatments for MFI,with a focus on therapies designed to enhance sperm quality and quantity.
HORMONAL ABNORMALITIES
In this specific sub-section, available evidence regarding the medical therapy used to restore or improve sperm quality and quantity in men with hypogonadotropic hypogonadism and hypergonadotropic hypogonadism is outlined. Although very different from an etiological and pathophysiological standpoint, these two conditions are characterized by circulating low T levels which negatively affects the process of spermatogenesis [3,4].
Hypogonadotropic hypogonadism
Hypogonadotropic hypogonadism or secondary hypogonadism indicates the inability of the hypothalamus to produce and release GnRH or of the pituitary gland to produce enough FSH and luteinizing hormone to sustain T production and spermatogenesis [9–11]. Etiologies span from congenital(i.e. Kallmann syndrome) to acquired ones (i.e.pituitary traumas, tumors, obesity and ageing) [4]. Consequently, men affected by hypogonadotropic hypogonadism face challenges in ensuring an adequate sexual development and spermatogenesis with the latter being completely impeded, leading to nonobstructive azoospermia (NOA) when congenital [11].
Gonadotropins in hypogonadotropic hypogonadism
* The recommended dose of hCG in men with congenital hypogonadotropic hypogonadism is 1000–2000 International Units (IU) of hCG (either intramuscular or subcutaneous) two or three times a week (BIW or TIW; Table 1 and Fig. 1). Conversely, different medications exist to ‘replace’ the missing action of FSH. Typically, although in clinical terms there is no preclusion to the concomitant use of the two drugs immediately, FSH therapy starts after 3–6 months after the initiation of hCG therapy [16]. Human menopausal gonadotropin (hMG) is one alternative for FSH treatment [17,18]. It is derived from the urine of postmenopausal women, who naturally have elevated levels of luteinizing hormone and FSH [17,18]. The typical regimen for hypogonadotropic hypogonadism consists of 75–150 IU of hMG subcutaneously or intramuscularly TIW [16,18,19]. Alternatively, recombinant FSH (rFSH) can also be used. Its regimen consists of 75–150 IU subcutaneously TIW [20,21]. Lastly, another alternative is represented by urofollitropin, which is a purified form of FSH that is manufactured by its extraction from the human urine. Its regimen is 75–150 IU subcutaneously TIW (Table 1) [22–24]. Although routinely used doses of FSH therapy have traditionally been used in everyday clinical practice, there is a lack of data to demonstrate that higher doses or several repetitions during the week may not be more effective.
* It is important to stress that patients may experience various side effects, such as nausea, breast enlargement or tenderness, fever, acne, weight changes, and headaches [14,25,26&&]. Additionally, discomfort at the injection site and abdominal pain have been reported as potential adverse reactions to these treatments as well (Table 1 and Fig. 1) [14,25,26&&].
Selective estrogen modulators for hypogonadotropic hypogonadism
* Clomiphene citrate can be prescribed ‘off-label’ at a dosage of 25mg taken orally once a day or every other day. The dose can be increased up to 50mg (Table 1 and Fig. 1) [29,36]. The most common side effects are self limited but can include nausea, vomiting, constipation, diarrhea, abdominal discomfort, hot flashes, insomnia, and increased breast tension with tenderness (Table 1) [29].
Aromatase inhibitors for hypogonadotropic hypogonadism
* As an off-label prescription, especially among patients with T/E2 less than 10, anastrozole (1 mg orally once a day or BIW or TIW) and letrozole (2.5 mg orally once a day) are the most commonly used aromatase inhibitors (Table 1 and Fig. 1) [38,39]. Common adverse events include nausea, hot flashes, headaches, and chest discomfort. Less frequent side effects include nervous system disorders, alopecia, bone problems, skin reactions, and liver function alterations [38,39].
Hypergonadotropic hypogonadism
Hypergonadotropic hypogonadism in men is instead characterized by low levels of circulating T along with elevated levels of gonadotropins [4]. This condition arises from a primary dysfunction of the gonads, specifically known as primary testicular failure [4]. This leads to insufficient T production,which is usually associated with spermatogenesis impairment [4]. In primary hypogonadism, the HPG axis remains intact and responds to the low levels of circulating T by increasing luteinizing hormone and FSH production [4]. Despite many cases are idiopathic in nature, common causes of hypergonadotropic hypogonadism include genetic disorders (e.g. Klinefelter syndrome), autoimmune diseases, infections (temporary hypogonadism), and certain treatments such as chemotherapy or radiation therapy [4]. The therapy of this condition, among those men interested in keeping their spermatogenesis relies on off-label protocols with SERMs, aromatase inhibitors and luteinizing hormone and FSH-like molecules (gonadotropins) [4]. As such, administering exogenous T (which is the standard of care of those not seeking to maintain fertility) would shut down the entire HPG axis thus inevitably resulting in severe oligospermia or azoospermia [4].
Gonadotropins for hypergonadotropic hypogonadism
* Instead, if a man has confirmed T deficiency with luteinizing hormone levels in the normal range, one could consider prescribing hCG at 1000 or 2000 IU subcutaneously/intramuscularly BIW or TIW to restore physiological circulating T levels (Table 2 and Fig. 1). This approach, although highly speculative because of the lack of RCTs or robust data, might theoretically increase ITT and boost spermatogenesis.
Selective estrogen modulators for hypergonadotropic hypogonadism
* Likewise, for hCG, if a man has confirmed T deficiency with luteinizing hormone levels in the normal range, one could consider prescribing clomiphene citrate 25–50 mg per os once a day or every other day to restore physiological circulating T levels (Table 2 and Fig. 1) [29]. Although this may hold true, no RCTs have been performed investigating SERMs only in hypergonadotropic hypogonadism, therefore, their use remains controversial, especially when it comes to improve semen parameters.
Aromatase inhibitors for hypergonadotropic hypogonadism
* Most studies in the literature focus on the Klinefelter syndrome population, although the rationale for aromatase inhibitor use can be applied ‘off-label’ to non-Klinefelter syndrome patients, once again despite the lack of robust RCTs. In this regard, it has been demonstrated that patients with a T/E2 ratio less than 10 benefit more from aromatase inhibitor therapy [43]. Lastly, aromatase inhibitor have also been successfully used in conjunction with SERMs and/or hCG in Klinefelter syndrome patients undergoing mTESE, improving sperm retrieval rates [40]. The most used aromatase inhibitors are anastrozole (1 mg orally once a day) and letrozole (2.5 mg once a day) (Table 2 and Fig. 1) [38,39]. The most frequent adverse events include nausea, hot flashes, headaches, and chest discomfort. Less common side effects include nervous system disorders, alopecia, bone problems, skin reactions, and alterations in liver function [38,39].
SUPRAPHYSIOLOGIC LEVELS OF HORMONES
In this specific sub-section, available evidence regarding the medical therapy used to restore or improve sperm quality and quantity in men with supraphysiologic levels of hormones (namely exogenous T use and hyperprolactinemia) is outlined.
Exogenous testosterone and anabolic steroid use
* Most men who become azoospermic because of prolonged exogenous T supplementation may restore spermatogenesis if exogenous T is stopped, and appropriate medical therapy is initiated (67–96%) [46,47]. A recent study of 45 men initially presenting with severe oligospermia or azoospermia because of chronic exogenous T use showed that, despite appropriate treatment regimens, about 50% failed to show substantial improvement in semen parameters after 6 months [44]. Some cases may see recovery in spermatogenesis up to 3 years after stopping exogenous T [48,49]. Nevertheless, treatment regimens to recover spermatogenesis after chronic exogenous T use aim to restore endogenous T production and stimulate spermatogenesis. As such, after stopping exogenous T/AAS, endogenous T production is stimulated via hCG 1000–2000 IU subcutaneously or intramuscularly BIW/TIW. Spermatogenesis stimulation can be achieved by adding one of the following: hMG: 75–150 IU subcutaneously or intramuscularly TIW or rFSH 75–150 IU subcutaneously TIW or urofollitropin 75–150 IU subcutaneously TIW or clomiphene citrate 25–50 mg orally every other day (Table 3 and Fig. 1) [50]. Even in this context, there is lack of RCTs and well designed observational studies, thus making these treatment regimens ‘off-label’.
Hyperprolactinemia
* The secretion of PRL follows a pulsatile pattern and can be influenced by factors such as sleep, stress, hypothyroidism, liver diseases ,pituitary tumors, and stimulation or injury to the chest wall [52&&,54]. Due to these variations, blood samples for PRL measurement should be collected after fasting and repeated at least once [55,56]. In men, prolonged elevated PRL levels are associated with T deficiency symptoms (e.g. sexual dysfunctions) and impaired spermatogenesis. In this regard, PRL inhibits GnRH secretion, thus impairing luteinizing hormone and FSH synthesis [52&&,54]. The most common cause for persistently elevated levels of PRL is pituitary adenoma (prolactinoma) [56]. If prolactinoma is confirmed via pituitary MRI, medical therapy consists of dopamine agonists to stop the over synthesis of PRL [57,58]. As such, dopamine agonists block directly the synthesis of PRL at the level of the lactotroph cells in the anterior pituitary. The most commonly used dopamine agonist is cabergoline (0.25mg TIW) (Table 3 and Fig. 1). The most common adverse effects include nausea, vomiting, heartburn, constipation, tiredness, dizziness, breast pain and burning, numbness, or tingling in the arms , hands, legs, or feet.
CONCLUSION
The present narrative review outlines the evidence in the context of medical therapy for MFI by providing clinical guidance on treatments for hormonal deficiencies (hypogonadotropic and hypergonadotropic hypogonadism, hyperprolactinemia) and supraphysiologic hormonal levels (exogenous T/AAS) to ameliorate sperm quality and quantity. Despite significant advancements have been made, most of these treatments remain based on small studies, thus making definitive recommendations inappropriate. As such, further research with well designed RCT is warranted.
