So, You Want To Have A Baby?

Most XXY’s who have contemplated having a baby will know of the high financial cost this can place on the household budget, but very few ever consider the longer term personal cost to health and psychological wellbeing. As documented here you will discover it is not the walk in the park that some doctors and advocacy groups will have you believe. As with all matters concerning XXY, we encourage you to do your own research to best ascertain what is right for you.

Non obstructive azoospermia, (NOA) is the most common cause of azoospermia. it is characterised by hypergonadotrophic hypogonadism, testicular failure, and impaired spermatogenesis. The recent development of surgical sperm retrieval techniques such as microsurgical testicular sperm extraction (mTESE) has, for the first time, allowed some men with non obstructive azoospermia to father biological children. It is common practice for endocrine stimulation therapies such asgonadotropin, selective oestrogen receptor modulators (SERMs) and aromatase inhibitors to be used prior to mTESE to increase intra-testicular testosterone synthesis with the aim of improving sperm retrieval rates; however, there is currently a paucity of data underpinning their safety and efficacy. We present two cases of men with NOA undergoing endocrine stimulation therapy and mTESE. We also discuss the current evidence and controversies associated with the use of hormonal stimulation therapy in couples affected by this severe form of male infertility.

Azoospermia is the absence of sperm in the ejaculate and has been reported to be present in 1% of the male population and 10-20% of men presenting to an infertility clinic. Secondary hypogonadism (hypogonadotrophic hypogonadism) associated azoospermia may be effectively treated with endocrine therapies such as gonadotrophin injections or pulsatile gonadotropin-releasing hormone (GnRH) pump administration, with a reported 50-70% of men subsequently producing sperm in their ejaculate. However, secondary hypogonadism has been reported to represent only a minority (2-3%) of cases of infertile men presenting with azoospermia. The vast majority of cases of azoospermia are due to a testicular pathology which may be either obstructive azoospermia (blockage of the ductal systems) or non-obstructive azoospermia (impairment of spermatogenesis).

Non obstructive azoospermia (NOA) accounts for 60% of all azoospermia and traditionally it has been viewed as an untreatable condition precluding fatherhood; however, recent advances in urological surgery have dramatically shifted the prognosis for affected men. Overall outcome data reports that microdissection testicular sperm extraction (mTESE) in men with NOA has reported sperm retrieval rates of up to 40-60%. A meta-analysis compared the sperm retrieval rates from mTESE, to traditional surgical techniques including conventional testicular sperm extraction (cTESE) and testicular sperm aspiration (TESA). The authors observed that mTESE was 50% more likely to successfully retrieve sperm than cTESE and cTESE was twice as likely to successfully retrieve sperm than TESA.

Consequently, mTESE is increasingly used as a first-line therapy for couples with infertility affected by NOA. This has led to several empiric pre-surgical hormonal stimulation approaches to treat men with NOA and hypogonadism (due to testicular failure) prior to mTESE. Whilst the use of hormone stimulation is recommended in cases of secondary hypogonadism, there is still debate surrounding its practice in men with NOA and primary hypogonadism prior to attempting surgical sperm retrieval. Advocates of hormone stimulation argue that hormone stimulation can improve surgical sperm retrieval rates and can shorten the timeframe for successful fertility outcomes

Whilst the use of hormone stimulation is recommended in cases of secondary hypogonadism, there is still debate surrounding its practice in men with NOA and Primary Hypogonadism (47XXY) prior to attempting surgical sperm retrieval

A 33-year old man with Klinefelter syndrome presented to the andrology clinic with the desire to start a family. His partner was 26 years old. The patient was diagnosed with Klinefelter syndrome (non-mosaic XXY) after investigations for symptomatic hypogonadism 2 years previously. He had been prescribed intramuscular testosterone undecanoate 1g every three months, but therapy was discontinued when he suffered bilateral deep vein thromboses (DVT) and a pulmonary embolism (PE) 3 years ago, for which he was prescribed anti-coagulated with warfarin. The patient had a history of attention deficit hyperactivity disorder (ADHD), but recalled normal pubertal development. There was no history of mumps, undescended testicles, testicular trauma, sexually transmitted infections or gonadotoxic drug use. The patient had reduced libido and early morning erections. The patient had a height of 1.84m and weight of 113kg, his BMI was 33.3 kg/m2. Physical examination revealed a sparse pattern of body hair and small testicles with 6mL volume bilaterally on ultrasound testing. The patient underwent two semen analyses which were reported azoospermia. Morning, fasted blood tests showed a serum FSH 22 IU/L, LH 16 IU/L, tT 5.2 nmol/l (150 ng/dL), SHBG 19 nmol/L, oestradiol 108 pmol/l, haematocrit 0.420 (L/L) (reference range 0.390-0.500) and platelets 278(x109/L) (reference range 130-370).

The patient had already experienced venous thromboembolic events (VTE) during androgen therapy; this history combined with his obesity would risk further VTE during endocrine stimulation and mTESE surgery. Nevertheless, the patient requested therapy in spite of being counselled of the risks of VTE. Anastrazole 1mg daily was commenced and repeated blood testing 3 months later were as follows: FSH 24.7IU/L, LH 17.2IU/L, testosterone 6.9 nmol/l (199ng/dL), oestradiol 101pmol/l, haematocrit 0.430(L/L). A further semen analysis reported azoospermia and the clinical decision was taken not to escalate endocrine therapy further due to the risk of VTE, and the patient underwent mTESE. Unfortunately, no sperm were identified, and testicular histology was reported as showing SCO (i.e. no evidence of germ cells or spermatogenesis). The couple remain childless and have no current plans for adoption or ART using donor sperm

The patient had already experienced Venous Thromboembolic Events (VTE) during androgen therapy; this history combined with his obesity would risk further VTE during endocrine stimulation and mTESE surgery. Nevertheless, the patient requested therapy in spite of being counselled of the risks of VTE.

Discussion
After puberty, men with Klinefelter syndrome typically undergo progressive testicular degeneration culminating in fibrosis of the seminiferous tubules and a reduced number of germ cells and spermatogonia. A meta-analysis of 37 studies and a cohort population of 1248 patients reported that the positive sperm retrieval rate for men with Klienfelter syndrome was 44%. This meta-analysis consisted exclusively of men with non-mosaic Klinefelters syndrome. Some men with mosaic Klinefelter syndrome may produce sperm in their ejaculate, non-mosaic cases are almost always azoospermic by adulthood. However, the surgical sperm retrieval rates are similar between mosaic and non-mosaic forms of Klinefelters syndrome in the available literature.

This patient has Klinefelter syndrome resulting in primary hypogonadism and NOA. Unlike the previous example, this patient had a normal TE ratio. SERMs inhibit oestrogen receptors in the hypothalamus and anterior pituitary, thereby downregulating oestrogen-mediated negative feedback on the hypothalamic-pituitary-gonadal (HPG) axis. SERMs upregulate gonadotropin secretion and thus promote testosterone production and spermatogenesis

Ramasamy et al. reported a cohort of 68 Klinefelter syndrome patients who underwent medical therapy (2-3 months testolactone (50-100mg) twice daily or 1 mg anastrozole daily with the addition of hCG or clomiphene if hormone parameters did not improve. The authors observed that in patients that had responded to hormone stimulation (i.e. those whose had a resultant serum tT of 250 ng/dl or higher) had a higher surgical sperm retrieval rate than men in whom post-treatment tT was less than 250 ng/dl (77% vs. 55%, p = 0.05). However, this study is a retrospective case series with no control group and no side effects profile is reported. Moreover, 26% of patients received more than one hormonal stimulation agent. Therefore, it is difficult to determine the relative potential benefits of individual hormone therapies from this analysis

Another aspect to consider in Klinefelter syndrome patients is the impact of testosterone replacement therapy (TRT) on fertility. Exogenous testosterone impairs spermatogenesis via negative feedback on gonadotrophin production. There are no controlled studies in the literature investigating the use of TRT in conjunction with other hormone stimulation agents in men with Klinefelter syndrome. There are two case series with a combined patient cohort of 12 men. Mehta et al. treated Klienfelter yndrome patients with topical testosterone (at varying doses aiming for a target serum testosterone >400ng/dl) and anastrozole 1mg daily prior to mTESE. The authors reported a successful sperm retrieval rate in 7/10 men. Herati et al.treated two Klienfelter syndrome patients with Testosterone enanthate (200 mg/mL per week) and hCG (3000 IU three times a week) prior to mTESE. Both patients had successful sperm retrieval. However, given the small sample sizes, retrospective nature and lack of control group in these studies we are unable to draw any meaningful conclusions about the use of TRT combined with other hormone agents in Klinefelter syndrome. Furthermore, there is data showing that previous exogenous testosterone use is associated with worse surgical sperm retrieval outcomes but again this is based on small cohort sizes.

However, given our understanding of the adverse effects of exogenous testosterone on spermatogenesis (as evidenced by male contraceptive trials) we would ideally advise cessation of all TRT prior to surgical sperm retrieval. This may be challenging in clinical practice because the patient may develop hypogonadal symptoms (such as loss of libido) in the washout period between TRT cessation and starting hormone stimulation therapy. Therefore, the authors would recommend preferential use of transdermal TRT preparations in hypogonadal men considering fertility because of the shorter half-life. If the patient presents whilst on Testosterone undecanoate we would start his hormone stimulation therapy at the time of the next testosterone undecanoate dose as this would prevent a washout period and hence prevent hypogonadal symptoms. However, these patients need close monitoring because they will be exposed to both exogenous testosterone and another hormone stimulation therapy agent and therefore are at higher risk of adverse events including VTE. The authors recommend monitoring Haemocrit levels and counselling the patients to avoid any additional VTE risk factors such as aviation travel.

However, these patients need close monitoring because they will be exposed to both exogenous testosterone and another hormone stimulation therapy agent and therefore are at higher risk of adverse events including VTE. The authors recommend monitoring Haemocrit levels and counselling the patients to avoid any additional VTE risk factors such as aviation travel

Within the literature, all of the VTE reports in Klinefelter syndrome patients on hormone stimulation therapy are related to those on exogenous testosterone. It has been reported that the risk of VTE is 20 times higher in men with Klinefelter syndrome compared to age-matched controls, and this is thought to be due to abnormalities in antithrombin III, proteins C and S and factor-V-Leiden levels. A retrospective Swedish study with a cohort of 1085 Klinefelter syndrome patients observed that the standardised incidence ratio for VTE was highest before the age of 30 years and declined with increasing age.

Published studies have yielded conflicting data regarding the effects of hormonal stimulation on VTE risk in men with Klinefelter syndrome. A recent study reported that neither testosterone therapy nor clomiphene increased the risk of VTE significantly beyond that of the general population in men without risk factors for VTE such as Klinefelter syndrome. Gluek et al. observed that in 6 men started on testosterone therapy with a background of Klinefelter syndrome and underlying thrombophilia, all men developed either a deep vein or mesenteric artery thrombosis. However, several studies in the field of dermatology have reported improvements in leg ulcers associated with reduction in prothrombotic factors in men with Klinefelter syndrome following testosterone replacement therapy. Taken together with published evidence to date, Case 2 highlights the need to assess risk of thrombosis prior to consideration of any endocrine stimulation therapy in any man with NOA (47XXY). It is known that men with Klinefelter syndrome have an elevated a priori risk of VTE; it is imperative to minimise concominant risk factors such as obesity and smoking, and disclose the uncertain risks of endocrine stimulation therapy in these men with Klinefelter syndome prior to mTESE. Randomised control trial data are required to quantify the risk burden of endocrine stimulation therapy prior to mTESE, including whether gonadotrophims, SERMs and aromatase inhibitors have differential risk profiles with regard to VTE risk.

Case 2 highlights the need to assess risk of thrombosis prior to consideration of any endocrine stimulation therapy in any man with NOA (47XXY). It is known that men with Klinefelter syndrome have an elevated a priori risk of VTE; it is imperative to minimise concominant risk factors such as obesity and smoking, and disclose the uncertain risks of endocrine stimulation therapy in these men with Klinefelter syndome prior to mTESE.

Conclusion
This article highlights two cases illustrating both ends of the spectrum of treatment outcomes, in a largely unproven but routinely used therapy given to highly vulnerable patients with infertility. There is a theoretical plausibility to the approach of hormonal stimulation prior to NOA which warrants further investigation. Furthermore, there are no alternative therapies available to optimise spermatogenesis in patients with NOA. However, there is a paucity of well-designed randomised controlled trials investigating the use of hormonal stimulation in men with NOA prior to surgical sperm retrieval of any type. Existing studies lack important clinical outcomes such as live birth and complication rate. In this context, the authors would not advocate hormone stimulation in every patient but rather in selective cases based on assessment of the potential risks and benefits of therapy. Selection for hormonal stimulation should incorporate risks and benefits of therapy. Female partners with an age under 35 years and regular periods have better ART outcomes when compared with older female partners and those with female factor infertility. A testicular volume <12.5ml and Sertoli cell syndrome histology are associated with a lower probability of sperm retrieval. Furthermore, a high risk of venous thromboembolism may be a reason to withhold hormonal stimulation. In couples where sperm donation is not feasible owing to religious or cultural views, there is an argument to offer hormone stimulation therapy in the hope of maximising the chances of successful sperm retrieval given the lack of alternatives. In summary, there are currently no factors for selecting en masse which men with NOA should receive hormonal stimulation; instead, a synthesis of these factors is required to agree with each patient whether hormonal therapy should be initiated. A survey of practicing American Urologists reported that approximately 65% of respondents would use hormone stimulation therapy in the management of male infertility, despite its poor evidence base. Increasing the price barrier of these drugs is one potential approach to discourage indiscriminate prescribing, and drive the generation of high quality trials data.

Existing studies lack important clinical outcomes such as live birth and complication rate. In this context, the authors would not advocate hormone stimulation in every patient but rather in selective cases based on assessment of the potential risks and benefits of therapy. Selection for hormonal stimulation should incorporate risks and benefits of therapy. For every couple a holistic approach is recommended taking into account the age of both partners, comorbidities and fertility status of the female partner. Furthermore, religious and cultural beliefs of couples may affect whether couples may accept alternatives to mTESE such as donor sperm IVF. We conclude that it is currently premature to either recommend or rule out hormonal stimulation prior to mTESE in men with NOA. An individualised approach is advisable; all patients should be counselled thoroughly on the inadequacies of the current literature and the potential benefits and side effects of hormone stimulation, to reach a shared decision on management

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