ENDOCRINE MANAGEMENT OF MALE INFERTILITY Francesco Lombardo

Transcription

1 ENDOCRINE MANAGEMENT OF MALE INFERTILITY Francesco Lombardo

2 Evidence-based medicine and male infertility therapy Control Randomization Placebo, cross over, double blind Inclusion and exclusion criteria Adequate number of patients Meta-analisys Avoid regression towards the mean

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4 Medical Treatment of Male Infertility Etiologic treatment Empirical treatment

5 INFECTIONS / INFLAMMATION OF THE GENITAL TRACT Male gamete crossing throughout a reproductive tract with infections/inflammation is subject to progressive damages deriving from alterations of epididymis seminal vesicles prostate

6 E. Coli Klebsiella Urethritis Epididymitis enterococco Proteus mirabilis Clamidia trachomatis Micoplasma Prostatitis

7 Fluoroquinolones They are a family of synthetic broadspectrum antibiotic drugs. They exert their antibacterial effect by preventing bacterial DNA from unwinding and duplicating. The majority of quinolones in clinical use are fluoroquinolones, which have a fluorine atom attached to the central ring system, typically at the 6-position or C-7 position. Most of them are named with the -oxacin suffix. They are often used for genitourinary infections, and are widely used in the treatment of hospital-acquired infections associated with urinary catheters. Resistance to quinolones can evolve rapidly, even during a course of treatment. Numerous pathogens, including Escherichia coli, commonly exhibit resistance.

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9 Kallikrein It is a polypeptide able to release 2 major kinins, kallidin and bradykinin, from seminal plasma kininogens. Activated kinins in semen affect sperm motility and metabolism BUT Controlled, randomized, placebocontrolled, double-blind trial including 114 couples (Glezermann M. et al., 1993) Controlled, randomized, placebocontrolled, double-blind trial including 91 couples (Keck C. et al., 1994, Yamamoto et al., 1996). No beneficial effect

10 Pentoxyphylline Belongs to the family of methylxanthines and act through the relaxation of vascular smooth muscles. It has been speculated that in men with OAT testicular circulation might be disturbed and would be improved by Pentoxyphylline. Extremely contrasting data from the literature but almost all open, uncontrolled trials. By and large there is neither evidence for circulatory disturbances in OAT nor is there proof for any clear therapeutic effects.

11 L-Arginine It might act on semen parameters through NO and consequent effect on circulation or direct on sperm. Some positive date in literature but not controlled trials. (it is one of the few drugs on sale in Italy with the specific indication Male infertility )

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14 Antioxidants

15 Sod CAT GSH Enzimatic Vitamine C Vitamine E Piruvate Glutathione Carnitine Non Enzimatic

16 ROS and spermatozoa

17 ROS and spermatozoa Under physiological conditions spermatozoa produce small amounts of ROS, which are necessary for capacitation and AR. Excessive amounts of ROS produced by white blood cells and the immature sperm can damage normal sperm inducing lipid peroxidation and damaging DNA.

18 Spermatozoa from many species incubated under specific conditions have the ability to produce small amounts of ROS without harming cell function and rather promoting signal transduction pathways associated with capacitation.

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24 Glutathione

25 Lenzi A., Culasso F., Gandini L., Lombardo F., Dondero F.: Placebo-controlled, doubleblinde, cross-over trial of glutathione therapy in male infertility. Hum Reprod, 8:1657, 1993.

26 Lenzi A., Culasso F., Gandini L., Lombardo F., Dondero F.: Placebo-controlled, doubleblinde, cross-over trial of glutathione therapy in male infertility. Hum Reprod, 8:1657, 1993.

27 Medical Treatment of Male Infertility Our experiences on carnitine

28 Carnitine Before entering the mitochondria fatty acids must be activated, that is to say, they must bind to the CoA to form acyl-coa. Long chain molecules of acyl-coa, are not able to cross the internal mitochondrial membrane; for this reason they need a transport mechanism.

29 CONTROLLED STUDIES ON CARNITINES IN OAT CONTROLLED CLINICAL TRIALS - PLACEBO CONTROLLED DOUBLE BLIND CROSS OVER TRIAL OF CARNITINE IN OAT PLACEBO CONTROLLED DOUBLE BLIND RANDOMIZED TRIAL OF CARNITINE and ACETYL-CARNITINE IN OAT

30 CONTROLLED STUDIES ON CARNITINES IN OAT CONTROLLED CLINICAL TRIALS - PLACEBO CONTROLLED DOUBLE BLIND CROSS OVER TRIAL OF CARNITINE IN OAT PLACEBO CONTROLLED DOUBLE BLIND RANDOMIZED TRIAL OF CARNITINE and ACETYL-CARNITINE IN OAT

31 SELECTION CRITERIA: patients free of general or endocrinological diseases, genital infections or obstructions, varicocele, cryptorchidism, testicular hypotrophy, antisperm Ab. NUMBER OF PATIENTS : 100 (age: 20-40; infertility: > 2 year) SEMINAL INCLUSION CRITERIA: concentration 10 x x 10 6 /ml; total motility: 10% - 30%; forward motility: < 15%; atypical forms > 70%; leukocytes: < 1 x 10 6 /ml; velocity: /sec; linearity: < 4.

32 THERAPY : Carnitine 2g/day or Placebo ANALYSES : Semen analysis, CASA, Carnitine and -Glycosidase, LPOp CHECKS : months -2, -1, 0, +2, +4, +6, +8 Titolo diagramma STUDY SCHEME months RUN IN 1 month RUN IN 2 month THERAPY or PLACEBO 2 months WASH OUT 2 months PLACEBO or THERAPY 2 months FOLLOW UP 2 months

33 VARIATION IN MOTILE SPERM x 10 6 / ml Motile Spermatozoa / ml (Mil./ml x % total sperm motility) Forward Motile Spermatozoa / ml (Mil./ml x % forward sperm motility) 10,0 7,5 9,0 7,4 7,0 5,0 7,2 5,8 5,0 5,4 5,6 Base L-Carnitine End Placebo 3,0 3,6 3,8 Base L-Carnitine End Placebo TOTAL SPERM MOTILITY F = Sig = FORWARD SPERM MOTILITY F = Sig = 0.026

34 Patients with less than 5,000,000 forward motility (% variation in sperm forward motility total / ejaculate Carnitine vs Placebo ) L- Carnitine Variation in % motility Placebo F = Sig =

35 CONTROLLED STUDIES ON CARNITINES IN OAT CONTROLLED CLINICAL TRIALS - PLACEBO CONTROLLED DOUBLE BLIND CROSS OVER TRIAL OF CARNITINE IN OAT PLACEBO CONTROLLED DOUBLE BLIND RANDOMIZED TRIAL OF CARNITINE and ACETYL-CARNITINE IN OAT

36 NUMBER OF PATIENTS : 60 (age: 20-40; infertility: > 2 year) SELECTION CRITERIA: patients free of general or endocrinological diseases, genital infections or obstructions, varicocele, cryptorchidism, testicular hypotrophy, antisperm Ab. SEMINAL INCLUSION CRITERIA: concentration 10 x x 10 6 /ml; total motility: 10% - 40%; forward motility: 5% - 20%; atypical forms > 80%; leukocytes: < 1 x 10 6 /ml.

37 THERAPY : Carnitine 2g/day and Acetyl-carnitine 1g/day or Placebo CHECKS : months -2, 0, +3, +6, +8 ANALYSES : Semen analysis, CASA, Carnitine and Acetyl-carnitine, LPOp. Titolo diagramma SCHEME OF THE STUDY months RUN IN THERAPY THERAPY FOLLOW UP 1 month 3 months 3 months 2 months RUN IN PLACEBO PLACEBO FOLLOW UP 1 month 3 months 3 months 2 months

38 Patient distribution and significance of differences according to the number of motile sperm / ejaculate Total motile sperm/ejaculate Forward motile sperm/ejaculate Numero di osservazioni Numero di osservazioni Mann-Whitney U Exact Sig. [2*(1-tailed Sig.)] Significantly higher increase in patients with T0 values of <5x10 6 total motile sperm/ejaculate (p = 0.018). Mann-Whitney U Exact Sig. [2*(1-tailed Sig.)] Significantly higher increase in patients with T0 values of <4x10 6 forward motile sperm/ejaculate (p = 0.028).

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42 Antiestrogens Clomiphene citrate Tamoxifen citrate Competitive binding to estradiol receptors at its target cells with subsequent increase in the secretion of GT and sex steroids.

43 Clomiphene citrate CC is a racemic mixture of two isoforms enclomiphene and zuclomiphene. It is a selective estrogen receptor modulator that blocks negative feedback at the level of the hypothalamus and the pituitary. This blockade of negative feedback indirectly enhances LH and FSH excretion from the anterior pituitary.

44 Clomiphene citrate Clomiphene citrate is tolerated well by most patients. More common side effects include gastrointestinal distress, dizziness, hair loss, gynecomastia, and minimal weight gain. There is also a 1.5% risk of visual disturbances such as blurred vision, photophobia, and diplopia although they are reversible with cessation of the medication.

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46 Aromatase Inhibitors Letrozole Anastrozole Aromatase, a cytochrome p450 enzyme, is present in the testes, prostate, brain, bone, and adipose tissue of men; it converts T and androstenedione to estradiol and estrone, respectively. Estradiol negatively feeds back on the hypothalamus and pituitary to reduce gonadotropic secretions ultimately affecting spermatogenesis

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48 The role of androgens in fertility Androgens produced by the testis and adrenal gland play an essential role in the development of male reproductive organs, puberty, male sexual function, and male fertility. It is estimated that low T or increased levels of LH are present in about 20% 30% of male infertility cases. Testosterone stimulates spermatogenesis, and the effect of LH stimulating spermatogenesis is mediated through intratesticular testosterone.

49 The role of androgens in fertility Inside Sertoli cells, T is bound to androgen receptors. When activated, these receptors result in the maintenance of spermatogenesis and inhibition of germ cell apoptosis. Abnormalities in AR may result in abnormal male sexual development, but also be a potential cause of male infertility. It has been found that the concentration of intratesticular T is times greater than normal serum levels. These high levels of intratesticular T can never be achieved by oral or parenteral administration of androgens.

50 The role of androgens in fertility Treatment with exogenous T and its metabolite, estrogen, would only suppress GnRH and LH at the hypothalamus and pituitary, respectively, which would ultimately suppress testicular T production.

51 Recovery of spermatogenesis after T cessation One of the first steps in the medical management of male factor infertility is to suspend exogenous T to treat symptomatic hypogonadism or in anabolic steroid. After a wash out period we can start the therapy with clomiphene citrate to expedite the recovery of spermatogenesis, sometimes associated with hcg therapy.

52 Human chorionic gonadotropin (hcg) hcg is an LH analog derived from urine or recombinant sources that stimulate intratesticular Leydig cell testosterone production.

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59 After three months of Maca administration, with the addition of oxigen allotropes, the patient s spermatozoa became vivacious enough to achieve implantation through the development of growing factors and to engage the process of a so long desired pregnancy with normal progress.

60 The alterations of the seminal fluid may be associated with four characteristic hormonal frameworks represented by: Normal Spermatogenesis Normal FSH Normal LH Normal TE Hypogonadotropic hypogonadism Low FSH Low LH Low/ normal TE Impaired Spermatogenesis High/ normal FSH Normal LH Low/ normale TE Hypegonadotropic hypogonadism High FSH High LH Low/ normal TE

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62 The most favorable condition from the therapeutic point of view is represented by Hypogonadotropic Hypogonadism. In this case you start treatment with gonadotropin, up to the potential appearance of sperm in the ejaculate Hypogonadotropic hypogonadism (Kallmann Syndrome) First try to obtain a good virilization of the hypogonadic patient Testosterone GnRH hmg/hcg rhfsh/hcg Then you can stimulate spermatogenesis up to the to the potential appearance of sperm in the ejaculate. About 2 ys till the appareance of spermatozoa

63 Hypogonadotropic hypogonadism Idiopathic Acquired Congenital Kallmann Isolated Deficit of GN Pituitary Trauma Pituitary Tumors Panhypopituitarism Anabolic steroids TREATMENT hcg UI twice a week hmg o FSH 150 UI thrice a week 4-8 weeks LEYDIG DEVELOPMENT 3-6 months SPERMATOGENESIS

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65 Klinefelter the same Sterility They have been reported tens of term pregnancies with healthy children without chromosomal abnormalities due to TESE + ICSI It should be remembered, however, that the depletion of testicular germ line is progressive and therefore it is recommended Early Diagnosis Cryopreservation Genetic Counseling

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67 LH FSH T

68 Physiologic functions of FSH In humans, gonadotropins are essential for the development and differentiation of spermatogonia, spermatocytes and the spermatids.

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72 Quantitative pooling of all available data showed no significant effect (OR 1.46; 95% CI ) on pregnancy rates in 234 couples.

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75 Medical Treatment of Male Infertility One of the most difficult problems in andrology is to translate the enormous quantity of knowledge about the pathophysiology of spermatogenesis and sperm function into a rationale for treatment of male infertility.

76 HUMAN FSH

77 Each subunit of FSH has two glycosylation sites on which are linked oligosaccharide chains Each chain is composed of different kinds of monosaccharides that may or may not end with a molecule of sialic acid

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80 NECESSITY TO IDENTIFY PARAMETERS PREDICTIVE OF A SUCCESS FSH LEVEL INHIBINA B LEVEL CYTOLOGY/HYSTOLOGY Foresta et al Foresta et al. Hum Reprod 1999, 14:

81 The lower limit of the range of FSH does not discriminate between fertile subjects and hypo-hypo infertile patients

82 Changes in the profile of FSH isoforms Mutations in the amino acid sequence of the receptor for FSH

83 FSH ISOFORMS AT DIFFERENT BIOLOGICAL ACTIVITY

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85 Changes in the profile of FSH isoforms Mutations in the amino acid sequence of the receptor for FSH

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87 The best-studied polymorphisms in the FSH receptor gene are Ala307Thr and Ser680Asn, which have been found to be in linkage disequilibrium in most of the studies. The amount of FSH needed to reach similar E2 levels in IVF cycles was higher in women that carried the Ser680 FSH receptor allele, suggesting that the Ser680 FSH receptor allele encodes a less active FSH receptor protein that is less sensitive to FSH than the Asn680 allele.

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90 No differenze nella distribuzione degli aplotipi

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100 Conclusions.AT LAST!!!!!!!

101 Any therapy in male infertility has to be considered experimental until it has proved its efficacy in controlled clinical studies. Placebo treatment differs from no treatment because a placebo can improve sperm parameters due to a psychological mechanism. rfsh was reputed effective when compared to a non treatment group, or ineffective when compared to a placebo-treated group. To define a drug as active, it should improve sperm patterns and pregnancy rates in at least one blind prospective, placebo-controlled trials. Inconclusive findings do not necessarily mean negative results (or no effect) Every therapy for male infertility must be accompanied by optimization of the female reproductive functions.