Urologia e Andrologia CTO – Istituti Clinici di

Perfezionamento MILANO

MIRCO CASTIGLIONI

La terapia medica del maschio infertile quando e

con quali molecole?

1. Aiutare la coppia ad ottenere una gravidanza spontanea

2. Downgrading della tecnica di PMA : ICSI IVF IUI

3. Migliorare le possibilità di successo di qualunque tecnica di PMA a cui si sottopone la coppia

1. la terapia può dare un miglioramento seminale stabile e pertanto buone probabilità di concepimento spontaneo in tempi ragionevolmente brevi ?

2. la terapia può dare un miglioramento temporaneo del seme che consenta il ricorso temporizzato alla fecondazione assistita a bassa (inseminazione omologa intrauterina = IUI) o ad alta tecnologia (FIVET o ICSI) o un down-grading della tecnica

3. - non è possibile realisticamente modificare la qualità del seme e la fecondazione assistita (FIVET o ICSI) rimane l'unico trattamento possibile;

4. in assenza di spermatozoi nel liquido seminale o in assenza di ejaculazione è ipotizzabile che una terapia medica sia efficace e quindi non si debba ricorrere al recupero chirurgico ?

• Infertility treatment should not start before 2 yr of unprotected intercourse, unless there are gross abnormalities found that exclude spontaneous pregnancy such as severe oligozoospermia or azoospermia, anovulation, tubal blockage, and female age >35 yr.

According to the Charlson Comorbidity Index, infertile men have a significantly higher rate of comorbidity compared with fertile controls (Salonia et al, 2009) Certain lifestyle factors sometimes influence semen quality, for example, obesity, alcohol abuse, heavy smoking, use of anabolic steroids, extreme sports (marathon training or excessive strength sports), and increase in scrotal temperature through thermal underwear, sauna or hot tube use, or occupational exposure to heat sources. Many drugs can affect spermatogenesis (Practise committee of American Society for Reproductive Medicine in collaboration with Society for Reproductive Endocrinology and Infertility Optimizing natural fertility Fert Steril, 90 (Suppl) (2008), pp. S1–S6)

During medical evaluation, a review of current and past medications and social habits is essential, as they may adversely affect fertility. In addition, knowledge of exposure is important for counseling regarding future fertility, as many such toxic exposures have reversible effects

The most important aspect for success of medical management of male infertility depends on the presence of a specific underlying etiology. This is in contrast to the poor pregnancy rate achieved with empirical hormonal therapy in cases of unexplained male subfertility, where the only abnormality is oligo-asthenozoospermia with normal hormonal profile.

• Ipogonadismo primario ipergonadotropo (es S. Klinefelter) : no terapia

• Ipogonadismo secondario ipogonadotropo: GnRH e/o gonadotropine sono in grado di indurre e mantenere la spermatogenesi.

• Prolattinoma: trattato efficacemente con agonisti della dopamina.

• MTS : la precoce terapia antibiotica è il trattamento di scelta.

• Aneiaculazione/eiaculazione retrograda: alfa-agonisti, anti-istaminici o anticolinergici utilizzati a volte con successo

It accounts for up to 2% of infertile men

In patients with hypogonadotropic hypogonadism, correction of underlying pathology, if possible may lead to restoration of spermatogenesis, and fertility. If not, gonadotropin replacement and gonadotropin releasing hormone (GnRH) pulsatile therapy are effective treatment options in these patients. Conventionally, treatment is started with human chorionic gonadotropin (HCG) with doses ranging from 1000 IU to 2500 IU thrice weekly given subcutaneously alone or in combination with follicle stimulating hormone (FSH). Usually, luteinizing hormone (LH) deficiency is corrected first until testosterone normalizes followed by addition of FSH to aid in spermatogenesis. HCG therapy is continued until the nadir testosterone levels (checked 48 hours after the testosterone injection) reach the mid normal range. After 6 months of therapy with HCG alone, if no sperm are detected on semen analysis, FSH is added to the treatment regime. This regime may take up to 1 to 2 years for its maximum efficacy on spermatogenesis. FSH may be given in the form of human menopausal gonadotropin (HMG) or recombinant FSH (rFSH) subcutaneously two to three times weekly. The usual dose of FSH for hypogonadotropic hypogonadism is around 75 IU of HMG or 100 to 150 IU of rFSH.

The best predictors of response to gonadotropin therapy are testicular volume and time of onset of gonadotropin deficiency (prepubertal vs. postpubertal). A testicular volume of 8 ml at the time of initiating treatment and postpubertal onset of gonadotropin deficiency is more likely to respond to gonadotropin therapy compared with prepubertal onset of disease and a testicular volume of 4 ml. Patients with cryptorchidism who have undergone orchidopexy had a poorer prognosis with negative outcome for restoring spermatogenesis. Pitteloud N, Hayes FJ, Dwyer A, Boepple PA, Lee H, Crowley WF., Jr Predictors of outcome of long-term GnRH therapy in men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2002;87:4128–36 Pulsatile GnRH therapy may be used for those patients with hypothalamic dysfunction, provided there is no primary pituitary pathology. It is typically started at an initial dose of 25 ng per kg per pulse delivered subcutaneously through a portable infusion pump every 2 hours. The dose of pulse is adjusted to maintain the testosterone levels in the mid normal range. Given the cumbersome nature of pulsatile GnRH therapy and need of portable infusion pump, the most preferred regime in cases of secondary testicular failure remains gonadotropin replacement therapy.

Aneiaculazione/eiaculazione retrograda

Various forms of gonadotropin treatment have been tried in idiopathic subfertility including HCG, HMG, and FSH alone or in different combinations. A meta-analysis of four randomized controlled studies using gonadotropin therapy in normogonadotropic male subfertility found significant increase in pregnancy rates within 3 months of initiating treatment. Most studies using FSH which showed positive response in terms of spermatogenesis and pregnancy rates with or without adjunctive ART had used higher doses of FSH compared to the conventional dose of 150 IU thrice a week.[Foresta et al, 2005] Hence, the dose of FSH needed in these groups of males with idiopathic subfertility may be higher

Attia et al, 2013

Encouraging preliminary data suggest a beneficial effect on live birth and pregnancy of gonadotrophin treatment formen with idiopathic male factor subfertility, but because the numbers of trials and participants are small, evidence is insufficient to allow final conclusions. Large multi-centre trials with adequate numbers of participants are needed.

Six RCTs with 456 participants. From the limited data, the live birth rate per couple randomly assigned (27% vs 0%; Peto odds ratio

(OR) 9.31, 95% confidence interval (CI) 1.17 to 73.75, one study, 30

participants, very low-quality evidence) and the spontaneous pregnancy rate per couple randomly assigned (16% vs

7%; Peto OR 4.94, 95% CI 2.13 to 11.44, five studies, 412 participants, I2 = 0%,

moderate-quality evidence) were significantly higher in men receiving gonadotrophin treatment than in men receiving placebo or no treatment. No significant difference between groups was noted when ICSI or IUI was performed

Clomiphene citrate and tamoxifen citrate are two estrogen receptor modulators with predominant antagonist activity. They block estrogen activity at the level of hypothalamus and anterior pituitary thereby abolishing the negative feedback exerted by estrogen. This results in increased gonadotropin secretion which could theoretically increase testosterone synthesis and enhance spermatogenesis. In view of their low cost, safety, and ease of oral administration, they were popular in the pre-ART era in the management of normogonadotropic male subfertility.

Several small observational and uncontrolled studies using clomiphene or tamoxifen in the management of idiopathic male subfertility have yielded mixed results with some showing improvement in spermatogenesis and pregnancy rates and others failing to prove any benefit. A meta-analysis studied 738 subfertile men with oligoastheno-zoospermia who received short-term treatment protocols with anti-estrogens. The pregnancy rate was 15.4% in the patient group versus 12.5% in the control group (odds ratio: 1.56; 95% CI: 0.99–2.19). The authors concluded that there were not enough data to support or disprove the utility of antiestrogens in the management of idiopathic male subfertility. It is possible that these agents in combination with other therapeutic modalities could be useful in the management of idiopathic male subfertility.

If a prolactin-secreting pituitary macro- or micro-adenoma is identified during evaluation of HH, then medical treatment with a dopamine receptor agonist is indicated. Cabergoline (0.125–1.0 mg twice weekly) is the preferred agent because it has the highest efficacy in normalizing prolactin levels and shrinking prolactin-secreting tumors, though bromocriptine is less expensive and also effective despite a higher risk of side effects. Reversal of infertility with dopamine agonist therapy occurs in 53% of cases.

Melmed S, Casanueva FF, Hoffman AR, Kleinberg DL, Montori VMet al. Diagnosis and

treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011; 96: 273–88.

Aromatase inhibitors reduce the conversion of androgens (testosterone and androstenedione) to estrogens (estradiol and estrone), thereby reducing the negative feedback on hypothalamus and pituitary. This leads to increase in gonadotropin secretion and increased androgen synthesis and secretion. Administration of aromatase inhibitors also restores the ratio of testosterone to estradiol (T: E2) to normal and has been thought to improve sperm concentration and motility. The T: E2 ratio has been shown to be significantly lesser in infertile men compared to normal controls (14.5 in fertile men versus 6.9 in men with nonobstructive azoospermia versus 4.4 in Klinefelter>s syndrome). Candidates for aromatase inhibition have usually been identified as men with serum T: E2 ratio less than 10. Aromatase inhibitors are available as steroidal (testolactone) and nonsteroidal (anastrozole) oral preparations. Both these drugs have been shown to improve the T: E2 ratio in several studies, however it's translation into clinical benefit is not conclusively proven. Improvement in semen parameters have been noticed in few studies. Improvement in pregnancy rates have not been studied adequately. Vandekerckhove P, Lilford R, Vail A, Hughes E. Clomiphene or tamoxifen for idiopathic oligo/asthenospermia. Cochrane Database Syst Rev. 2000;2

• Obesity is a pandemic and is associated with multiple medical problems including subfertility. Male obesity has been associated with altered semen parameters and reproductive hormonal levels, including a reduced testosterone:estradiol (T:E2) ratio. Treatment methods employed for obesity-related male subfertility include gonadotropin administration, weight loss, and aromatase inhibitors. Letrozole is a highly effective nonsteroidal aromatase inhibitor that has been used to treat male subfertility in several case series with promising results. Adequately designed randomized controlled studies are needed to produce evidence-based data on the role of aromatase inhibitors in male subfertility management and evaluate the side-effect profile.

Hum Reprod. 2014 Feb;29(2):193-200.

The relationship between male BMI and

waist circumference on semen quality: data

from the LIFE study.

Eisenberg ML(1), Kim S, Chen Z,

Sundaram R, Schisterman EF, Buck Louis

GM.

INFERTILITA’ IDIOPATICA (da stress ossidativo ?)

La maggior parte dei lavori attribuisce grande rilievo allo sbilancio tra attività antiossidante (TAC) e ROS nel determinismo dello stress ossidativo

• sperm DNA fragmentation has been recognized as one of the important causes of reduced fertility potential. Elevated sperm DNA fragmentation rates also significantly diminish the chance of success in assisted pregnancies. Sperm DNA damage can impair fertilization, disrupt embryonic development, and increase rates of miscarriage and poor conception rates. Newer studies suggest the possibility of an increased risk of childhood cancer when an embryo develops from DNA-damaged sperm. There is limited data from large, randomized, controlled trials to support improvement in male fertility with current interventions such as antioxidant therapy, varicocelectomy, and antibiotics treatment in genital tract infections. Nonetheless, research efforts have shown improvements in semen parameters and these interventions are low risk. Therefore, when the external risk factors are known, every effort should be made to minimize sperm DNA damage.

Sperm quality and DNA integrity in the adult male can be affected by environmental, occupational, and lifestyle factors. However, in addition to intoxication of industrial or accidental origin, smoking is the only well-documented intoxicating factor with a detrimental effect on human fertility M. Zitzmann, C. Rolf, V. Nordhoff, G. Schräder, M. Rickert-Föhring, P. Gassner, et al. Male smokers have a decreased success rate for in vitro fertilization and intracytoplasmic sperm injection Fertil Steril, 79 (Suppl. 3) (2003), pp. S1550–S1554

L. Gandini, F. Lombardo, A. Lenzi, F. Culasso, R. Pacifici, P. Zuccaro, et al. The in-vitro effects of nicotine and cotinine on sperm motility Hum Reprod, 12 (1997), pp. 727–733

• Oxidative stress can contribute to impairment in spermatogenesis leading to male-factor infertility. The effectiveness of various antioxidants (such as carnitine, vitamin C, vitamin E, selenium, carotenoids, glutathione, N-acetylcysteine, zinc, folic acid, and coenzyme Q10) is variable with respect to improving semen parameters and pregnancy rates. A recent Cochrane review determined that men taking antioxidants had a statistically significant increase in both live birth rates and pregnancy rates. For those undergoing assisted reproduction, the odds ratio that antioxidant use would improve pregnancy rates was 4.18, with a 4.85-fold improvement in live birth rate also noted. Further investigation with randomized, controlled clinical trials is needed to confirm the safety and efficacy of antioxidant supplementation in the medical management and treatment of male infertility.

The present study shows that one quarter

of men in couples

diagnosed as ‘unexplained infertile’

according to traditional

diagnostic methods have a DFI level 20%,

previously found to

be associated with a decreased fertility in

vivo

Even if beneficial effects were reported in a few cases of male infertility, more multicentre, double-blind studies performed with the same criteria are necessary for an increased understanding of the effects of various antioxidants on fertility.

Lombardo et al, 2011

Effect of oral supplementation with antioxidants for male partners of couples undergoing assisted reproduction techniques (ART).

34 trials with 2876 couples in total. Three trials reported live birth. Men taking oral antioxidants had an associated statistically significant increase in live birth rate (pooled odds ratio (OR) 4.85, 95% CI 1.92 to 12.24; P = 0.0008 )when compared with the men taking the control.

Pregnancy rate: 15 trials including 964 couples. Antioxidant use was associated with a statistically significant increased pregnancy rate compared to control (pooled OR 4.18, 95% CI 2.65 to 6.59; P < 0.00001).

The evidence suggests that antioxidant supplementation in subfertile males may improve the outcomes of live birth and pregnancy rate for subfertile couples undergoing ART cycles

Unfortunately, this meta-analysis could not identify the specific agents or dosage to recommend for treatment of infertile men.

Showell et al, 2011

La durata dell'infertilità è giustificata dalla sola inadeguatezza dello spermiogramma?

La correzione di una disovulazione o di un altro fattore femminile correggibile con terapie mediche o chirurgiche potrebbe essere sufficiente per raggiungere un concepimento spontaneo, senza intervenire sul maschio?

• There is no evidence that hormonal therapies, such as human menopausal gonadotrophin (hMG)/human chorionic gonadotrophin (hCG), androgen, antioestrogens (clomiphene and tamoxifen), prolactin inhibitors (bromocriptine), and steroids improve pregnancy rates in partners of men with idiopathic OAT. However, hypogonadotrophic hypogonadism can be treated medically. The standard treatment is hCG, with the later addition of hMG or recombinant FSH, depending on initial testicular volume. In some cases of idiopathic hypogonadotrophic hypogonadism, spontaneous reversibility of reproductive function has been observed. (Pitteloud et al, 2005)

• A wide variety of empirical drug approaches have been performed. However, the scientific evidence for such empirical approaches is low. Bromocriptine, hCG/hMG, α-blockers, systemic corticosteroids, and magnesium supplementation are not effective for the treatment of idiopathic OAT. Androgens are strictly contraindicated. Recombinant FSH, folic acid with zinc, or antioestrogens may be beneficial in some patients. Cochrane analysis has shown that men taking oral antioxidants had a significant increase in live-birth rate (pooled odds ratio: 4.85; 95% CI, 1.92–12.24; p = 0.0008, I2 = 0%) when compared with men taking placebo. No studies have reported evidence of harmful side effects of antioxidant therapy. The evidence suggests that antioxidant supplementation in subfertile men may improve the outcomes of live birth and pregnancy rates for subfertile couples undergoing assisted reproduction techniques (ART) cycles. This conclusion is based on only 20 live births from a total of 214 couples. Further head-to-head comparisons are necessary to identify the superiority of one antioxidant over another (Showell et al, 2011)

In many subfertile couples, there are no identifiable female factors and

either no modifiable male factors are identifiable, or subfertility persists

despite treatment of an identified male factor. Medical treatment

could enhance natural conception or improve outcomes with assisted

reproduction. However, medical therapy should not be used in

patients with known genetic factors such as karyotype anomalies or

Y chromosome deletion. Therefore, it is essential to perform a complete

diagnostic workup of the male before deciding on which men will

respond to medical therapy and those who need to be referred to

assisted reproduction. Couples who elect to proceed with empiric

medical treatment must be counseled that such treatment may be

ineffective and could lead to delays in assisted reproduction that

may adversely affect outcome.

Componente essenziale in tale lavoro è anche il fornire alle coppie in esame informazioni precise e veritiere in merito alle aspettative realistiche di successo dei programmi terapeutici proposti.