hCG

Anabolic steroid-induced hypogonadism: diagnosis and treatment.

To develop an understanding of hypogonadal men with a history of anabolic-androgenic steroid (AAS) use and to outline recommendations for management. Review of published literature and expert opinions. Intended as a meta-analysis, but no quality studies met the inclusion criteria. Not applicable. Men seeking treatment for symptomatic hypogonadism who have used nonprescribed AAS. History and physical examination followed by medical intervention if necessary. Serum testosterone and gonadotropin levels, symptoms, and fertility restoration. Symptomatic hypogonadism is a potential consequence of AAS use and may depend on dose, duration, and type of AAS used. Complete endocrine and metabolic assessment should be conducted. Management strategies for anabolic steroid-associated hypogonadism (ASIH) include judicious use of testosterone replacement therapy, hCG, and selective estrogen receptor modulators. Although complications of AAS use are variable and patient specific, they can be successfully managed. Treatment of ASIH depends on the type and duration of AAS use. Specific details regarding a patient's AAS cycle are important in medical management.

Testosterone replacement therapy and spermatogenesis in reproductive age men.

Testosterone has a pivotal role in spermatogenesis, erectile function, libido and expression of secondary sexual characteristics. The prevalence of symptomatic, laboratory-proven testosterone deficiency increases with age and is often treated with testosterone replacement therapy (TRT). Treatment with exogenous androgens suppresses gonadotropin levels, inhibits endogenous testosterone production and drastically reduces intratesticular testosterone, consequently impairing spermatogenesis. Sperm production often slowly resumes after TRT cessation. However, the rate of recovery shows highly variable kinetics that might complicate family planning. Medical therapies (including aromatase inhibitors and selective oestrogen receptor antagonists) and exogenous gonadotropins (including human chorionic gonadotropin and follicle-stimulating hormone) may be used to preserve or restore spermatogenesis in select populations receiving TRT. Exogenous testosterone is contraindicated in men trying to conceive, but new short-acting formulations, including oral testosterone undecanoate and nasal testosterone gel, might incompletely suppress the hypothalamic-pituitary-gonadal axis and partially preserve spermatogenesis.

A Current Perspective on Delayed Puberty and Its Management.

Delayed puberty is defined as the lack of development of secondary sex characteristics in childhood. Based on a review of the literature, delayed puberty can be divided into three main categories: (i) hypergonadotropic hypogonadism (congenital and acquired); (ii) permanent hypogonadotropic hypogonadism (congenital and acquired); and (iii) transient hypogonadotropic hypogonadism [constitutional delay of growth and puberty (CDGP) and functional hypogonadotropic hypogonadism]. CDGP is the most common cause of hypogonadism in both males and females, accounting for 60% and 30% respectively. Testosterone is the primary treatment for male hypogonadism, while estrogen and progesterone are used for female hypogonadism. However, in recent years, physiological induction therapy protocols such as human chorionic gonadotropin (hCG) monotherapy, hCG + follicle-stimulating hormone combined therapy, and gonadotropin-releasing hormone infusion have been recommended for the treatment of hypogonadotropic hypogonadism to increase long-term fertility success. There is no clear consensus on treatment protocols for physiological induction treatment and its effect on fertility. This review will discuss the clinical approach to hypogonadism, as well as traditional and physiological induction protocols.

Gonadotropins for pubertal induction in males with hypogonadotropic hypogonadism: systematic review and meta-analysis.

Hypogonadotropic hypogonadism is characterized by inadequate secretion of pituitary gonadotropins, leading to absent, partial, or arrested puberty. In males, classical treatment with testosterone promotes virilization but not testicular growth or spermatogenesis. To quantify treatment practices and efficacy, we systematically reviewed all studies investigating gonadotropins for the achievement of pubertal outcomes in males with hypogonadotropic hypogonadism. Systematic review and meta-analysis. A systematic review of Medline, Embase, Global Health, and PsycINFO databases in December 2022. Risk of Bias 2.0/Risk Of Bias In Non-randomized Studies of Interventions/National Heart, Lung, and Blood Institute tools for quality appraisal. Protocol registered on PROSPERO (CRD42022381713). After screening 3925 abstracts, 103 studies were identified including 5328 patients from 21 countries. The average age of participants was <25 years in 45.6% (n = 47) of studies. Studies utilized human chorionic gonadotropin (hCG) (n = 93, 90.3% of studies), human menopausal gonadotropin (n = 42, 40.8%), follicle-stimulating hormone (FSH) (n = 37, 35.9%), and gonadotropin-releasing hormone (28.2% n = 29). The median reported duration of treatment/follow-up was 18 months (interquartile range 10.5-24 months). Gonadotropins induced significant increases in testicular volume, penile size, and testosterone in over 98% of analyses. Spermatogenesis rates were higher with hCG + FSH (86%, 95% confidence interval [CI] 82%-91%) as compared with hCG alone (40%, 95% CI 25%-56%). However, study heterogeneity and treatment variability were high. This systematic review provides convincing evidence of the efficacy of gonadotropins for pubertal induction. However, there remains substantial heterogeneity in treatment choice, dose, duration, and outcomes assessed. Formal guidelines and randomized studies are needed.

Optimal restoration of spermatogenesis after testosterone therapy using human chorionic gonadotropin and follicle-stimulating hormone.

To study improvements in spermatogenesis in men with a history of testosterone therapy using a novel fertility treatment regimen. A single-center retrospective cohort analysis. Seventy-seven men with previous testosterone use seeking fertility treatment from January 2020 to March 2024. A treatment regimen of 3,000 IU of human chorionic gonadotropin (hCG) and 75 IU of follicle-stimulating hormone (FSH) three times a week was used. The primary outcome measured was change in sperm concentration during hCG/FSH therapy. The secondary outcome measured was whether concurrent testosterone therapy during hCG/FSH therapy affected recovery of spermatogenesis. Within the entire cohort (n = 77), 74% of men demonstrated improvements in their sperm concentrations. There was not a significant difference in recovery of sperm concentration in men who stayed on testosterone therapy during hCG/FSH reboot (no testosterone therapy [n = 50], 74% improved, vs. concurrent testosterone therapy [n = 27], 74% improved). We report optimal recovery of spermatogenesis with hCG/FSH therapy in men with infertility with a history of testosterone use. Concurrent testosterone therapy does not impede hCG/FSH-mediated spermatogenic recovery.

Hormone-Based Treatments in Subfertile Males.

Subfertility is defined as the condition of being less than normally fertile though still capable of effecting fertilization. When these subfertile couples seek assistance for conception, a thorough evaluation of male endocrine function is often overlooked. Spermatogenesis is a complex process where even subtle alterations in this process can lead to subfertility or infertility. Male endocrine abnormalities may suggest a specific diagnosis contributing to subfertility; however, in many patients, the underlying etiology is still unknown. Optimizing underlying endocrine abnormalities may improve spermatogenesis and fertility. This manuscript reviews reproductive endocrine abnormalities and hormone-based treatments.

Alternatives to Testosterone Therapy: A Review.

Although testosterone therapy (TTh) is an effective treatment for hypogonadism, recent concerns regarding its safety have been raised. In 2015, the US Food and Drug Administration issued a warning about potential cardiovascular risks resulting from TTh. Fertility preservation is another reason to search for viable alternative therapies to conventional TTh, and in this review we evaluate the literature examining these alternatives. To review the role and limitations of non-testosterone treatments for hypogonadism. A literature search was conducted using PubMed to identify relevant studies examining medical and non-medical alternatives to TTh. Search terms included hypogonadism, testosterone replacement therapy, testosterone therapy, testosterone replacement alternatives, diet and exercise and testosterone, varicocele repair and testosterone, stress reduction and testosterone, and sleep apnea and testosterone. Review of peer-reviewed literature. Medical therapies examined include human chorionic gonadotropins, aromatase inhibitors, and selective estrogen receptor modulators. Non-drug therapies that are reviewed include lifestyle modifications including diet and exercise, improvements in sleep, decreasing stress, and varicocele repair. The high prevalence of obesity and metabolic syndrome in the United States suggests that disease modification could represent a viable treatment approach for affected men with hypogonadism. These alternatives to TTh can increase testosterone levels and should be considered before TTh. Lo EM, Rodriguez KM, Pastuszak AW, Khera M. Alternatives to Testosterone Therapy: A Review. Sex Med Rev 2018;6:106-113.

Human chorionic gonadotropin treatment: a viable option for management of secondary hypogonadism and male infertility.

Introduction: Low testosterone and its symptoms is a condition affecting many males with severe repercussions on health. Testosterone affects metabolism, bones, joints, and ligaments, the cardiovascular system, liver, sexual functions, muscle mass, and the nervous system. Nowadays, due to recent research showing the benefits of testosterone replacement therapy, this treatment is gaining in popularity among aging men. However, testosterone replacement can increase the risk of infertility. Areas covered: Human chorionic gonadotropin (HCG) is used in the treatment of male infertility due to its luteinizing hormone (LH)-like action triggering testosterone and sperm production. Due to these positive effects on testosterone production, HCG has also been used to treat secondary hypogonadism. In this review, based on a literature review for the years 1977-2020 via Google Scholar, we summarize the current research on HCG as treatment for patients suffering from low testosterone and provide an overview of the pros and contras for HCG therapy as compared to testosterone replacement therapy for the treatment of secondary hypogonadism. Expert opinion: The testosterone and sperm production triggering effects of HCG without the side effects on fertility seen in testosterone replacement therapy make HCG therapy a prime candidate for patients suffering from secondary hypogonadism.

Testosterone and Male Infertility.

Hypogonadism and its therapies have a significant impact on male fertility potential. It is necessary to determine the etiology to treat and counsel the patient appropriately on therapeutic options. For the hypogonadal male on exogenous testosterone, management should begin with&#xa0;cessation of the exogenous testosterone and supplemental subcutaneous human chorionic gonadotropin and an oral follicle-stimulating hormone (FSH)-inducing agent to allow reestablishment of the hypothalamic-pituitary-gonadal axis and spermatogenesis. Further supplemental therapy with recombinant FSH in some patients may be necessary to achieve optimal semen parameters.

Male hypogonadism: therapeutic choices and pharmacological management.

Male hypogonadism, defined as an inadequate testosterone production, recognizes a testicular (primary hypogonadism) or a hypothalamic-pituitary dysfunction (central hypogonadism), although combined forms can also occur. Moreover, it has been known that intensive exercise training might be a cause of functional hypogonadism. Many therapeutic choices are currently available, depending on the timing of hypogonadism onset and fertility issue. The aim of this review was to comprehensively supply therapeutic options and schemes currently available for male hypogonadism, including pharmacological management of primary and central forms. Evidence on testosterone formulations, human chorionic gonadotropin, selective estrogen receptor modulators and aromatase inhibitors will be provided.

Human chorionic gonadotropin-based clinical treatments for infertile men with non-obstructive azoospermia.

Spermatogenesis is primarily controlled by follicle-stimulating hormone and luteinizing hormone-driven testosterone. Luteinizing hormone acts on the Leydig cells, stimulating steroid production, predominantly testosterone, and activating critical inter-related spermatogenesis regulatory pathways. Despite evidence that exogenous gonadotropins containing luteinizing hormone activity, particularly human chorionic gonadotropin, can effectively restore spermatogenesis in azoospermic males with hypogonadotropic hypogonadism, the use of these drugs to treat other forms of non-obstructive azoospermia is the subject of an ongoing debate. In this review, we delve into the molecular properties and functions of human chorionic gonadotropin in spermatogenesis regulation and explore available preparations for therapeutic use. We examine the evidence regarding the effectiveness of human chorionic gonadotropin in treating infertility in men with pre-testicular or testicular non-obstructive azoospermia and, additionally, identify the main areas for future research. Our review highlights the critical role of luteinizing hormone activity in spermatogenesis and emphasizes the potential of human chorionic gonadotropin in treating male infertility. The variation in the characteristics of patients with non-obstructive azoospermia underscores the importance of assessing hormonal profiles when contemplating hormonal treatment for these patients. A novel stratification of male infertility patients, the APHRODITE criteria, which considers clinical and laboratory indicators, may assist in identifying individuals who could benefit from human chorionic gonadotropin therapy. While accumulating evidence suggests promising venues for pharmacological treatment in male infertility, including non-obstructive azoospermia, further research is required to completely elucidate the mechanisms underlying the effects of exogenous gonadotropins with luteinizing hormone activity on sperm production and to establish the most effective dosages and treatment durations.

Hormone substitution in male hypogonadism.

Male hypogonadism is characterised by androgen deficiency and infertility. Hypogonadism can be caused by disorders at the hypothalamic or pituitary level (hypogonadotropic forms) or by testicular dysfunction (hypergonadotropic forms). Testosterone substitution is necessary in all hypogonadal patients, because androgen deficiency causes slight anemia, changes in coagulation parameters, decreased bone density, muscle atrophy, regression of sexual function and alterations in mood and cognitive abilities. Androgen replacement comprises injectable forms of testosterone as well as implants, transdermal systems, sublingual, buccal and oral preparations. Transdermal systems provide the pharmacokinetic modality closest to natural diurnal variations in testosterone levels. New injectable forms of testosterone are currently under clinical evaluation (testosterone undecanoate, testosterone buciclate), allowing extended injection intervals. If patients with hypogonadotropic hypogonadism wish to father a child, spermatogenesis can be initiated and maintained by gonadotropin therapy (conventionally in the form of human chorionic gonadotropin (hCG) and human menopausal gonadotropin (hMG) or, more recently, purified or recombinant follicle stimulating hormone (FSH)). Apart from this option, patients with disorders at the hypothalamic level can be stimulated with pulsatile gonadotropin-releasing hormone (GnRH). Both treatment modalities have to be administered on average for 7-10 months until pregnancy is achieved. In individual cases, treatment may be necessary for up to 46 months. Testosterone treatment is interrupted for the time of GnRH of gonadotropin therapy, but resumed after cessation of this therapy.

Preserving fertility in the hypogonadal patient: an update.

An increasing number of young and middle-aged men are seeking treatment for symptoms related to deficient levels of androgens (hypogonadism) including depression, loss of libido, erectile dysfunction, and fatigue. The increase in prevalence of testosterone supplementation in general and anabolic steroid-induced hypogonadism specifically among younger athletes is creating a population of young men who are uniquely impacted by the testicular end-organ negative consequences of exogenous steroid use. Exogenous testosterone therapy can alter the natural regulation of the hypothalamic-pituitary-gonadal axis leading to impaired spermatogenesis with azoospermia being a serious possible result, thus rendering the individual infertile. For men of reproductive age who suffer from hypogonadal symptoms, preservation of fertility is an important aspect of their treatment paradigm. Treatment with human chorionic gonadotropin (hCG) has shown the ability not only to reverse azoospermia brought on by testosterone supplementation therapy but also to help maintain elevated intratesticular testosterone levels. In addition, selective estrogen receptor modulators, often used with hCG have been shown both to elevate total testosterone levels and to maintain spermatogenesis in hypogonadal men.

Body Image Disorders and Anabolic Steroid Withdrawal Hypogonadism in Men.

Hypogonadism commonly occurs during withdrawal from anabolic-androgenic steroid (AAS) use, particularly when users have been taking AAS for prolonged periods. Mounting evidence now suggests that AAS-induced hypogonadism may persist for months or even years after last AAS use, and in some cases may be partially or completely irreversible. Treatment with human chorionic gonadotropin and clomiphene may help to restore hypothalamic-pituitary-testicular axis function, and these substances are widely used illicitly by AAS users at the end of a course of AAS as so-called postcycle therapy. Many endocrinologists still have only limited experience in diagnosing and treating AAS-induced hypogonadism.

Male infertility and gonadotropin treatment: What can we learn from real-world data?

Gonadotropin therapy to treat specific male infertility disorders associated with hypogonadotropic hypogonadism is evidence-based and effective in restoring spermatogenesis and fertility. In contrast, its use to improve fertility in men with idiopathic oligozoospermia or nonobstructive azoospermia remains controversial, despite being widely practiced. The existence of two major inter-related pathways for spermatogenesis, including FSH and intratesticular testosterone, provides a rationale for empiric hormone stimulation therapy in both eugonadal and hypogonadal males with idiopathic oligozoospermia or nonobstructive azoospermia. Real-world data (RWD) on gonadotropin stimulating for these patient subsets, mainly using human chorionic gonadotropin and follicle-stimulating hormone, accumulated gradually, showing a positive therapeutic effect in some patients, translated by increased sperm production, sperm quality, and sperm retrieval rates. Although more evidence is needed, current insights from RWD research indicate that selected male infertility patients might be managed more effectively using gonadotropin therapy, with potential gains for all parties involved.

Recovery of reproductive function following androgen abuse.

To summarize recent data on the adverse reproductive consequences of androgen abuse, focusing on the recovery of reproductive function following androgen discontinuation. Evidence is mostly based on case reports and observational studies. Androgen abuse leads to a state of hypogonadotropic hypogonadism associated with impaired spermatogenesis, testicular atrophy, gynecomastia as well as menstrual irregularities, virilization and subfertility. Recovery of the hypothalamic-pituitary-gonadal axis following androgen withdrawal depends on the type and characteristics of androgen administration (dose, duration of use) as well as those of the user (age, previous reproductive function). Biochemical and clinical features of hypogonadism may be evident months or even years following androgen discontinuation. To prevent androgen-related adverse effects and accelerate recovery of gonadal function, users take androgens in a cyclical fashion and use drugs such as human chorionic gonadotropin, antiestrogens and aromatase inhibitors, even though there is limited evidence to support efficacy of these strategies. As few studies refer to female androgen users, there is a lack of data concerning recovery from androgen-related reproductive side effects in women. Androgen abuse has profound and commonly under-recognized effects on the reproductive system; recovery following androgen withdrawal may be prolonged and occasionally incomplete.

A combined analysis of data to identify predictive factors for spermatogenesis in men with hypogonadotropic hypogonadism treated with recombinant human follicle-stimulating hormone and human chorionic gonadotropin.

To compare the efficacy and safety of recombinant human FSH (r-hFSH) and hCG treatment for male hypogonadotropic hypogonadism (HH) in different populations and to identify characteristics predictive of spermatogenesis. A combined analysis of data from four clinical trials. Phase III, open-label, noncomparative studies with similar designs conducted in Australia, Europe, Japan, and the United States. One hundred men with complete idiopathic or acquired HH. Pretreatment with hCG for 3-6 months, followed by combination therapy with hCG and r-hFSH (150 IU three times weekly) for up to 18 months. Doses of r-hFSH were adjusted according to spermatozoa count until the maximum dose was reached. The primary efficacy endpoint was a spermatozoa concentration of >or=1.5 x 10(6)/mL. A total of 81 men remained azoospermic but achieved normal serum T concentrations after hCG pretreatment. Of these, 68 (84.0%) achieved spermatogenesis and 56 (69.1%) achieved spermatozoa concentrations >or=1.5 x 10(6)/mL. Large baseline mean testicular volume, low body mass index, and advanced sexual maturity were predictors of good response to therapy. Similar treatment responses were observed across different study populations. R-hFSH (combined with hCG) is effective for the restoration of fertility in the majority of men with HH.

The interrelationships between thyroid dysfunction and hypogonadism in men and boys.

Thyroid hormone deficiency affects all tissues of the body, including multiple endocrine changes that alter growth hormone, corticotrophin, glucocorticoids, and gonadal function. Primary hypothyroidism is associated with hypogonadotropic hypogonadism, which is reversible with thyroid hormone replacement therapy. In male children follicle-stimulating hormone (FSH) is elevated and associated with testicular enlargement without virilization. Men with primary hypothyroidism have subnormal responses of luteinizing hormone (LH) to gonadotropin-releasing hormone (GnRH) administration and normal response to human chorionic gonadotropin (hCG). Free testosterone concentrations are reduced in men with primary hypothyroidism and thyroid hormone replacement normalizes free testosterone concentrations. In men with primary hypothyroidism, prolactin is not consistently elevated (except in men and children with longstanding severe primary hypothyroidism), but prolactin declines following thyroid hormone replacement therapy. Thyroid hormone is known to affect sex hormone-binding hormonal globulin (SHBG) concentrations. Men with hyperthyroidism have elevated concentrations of testosterone and SHBG. Thyroid hormone therapy in normal men may also duplicate this elevation. In addition estradiol elevations are observed in men with hyperthyroidism, and gynecomastia is common in them as well. In contrast to patients with primary hypothyroidism, men with hyperthyroidism exhibit hyperresponsiveness of LH to GnRH administration and subnormal responses to hCG. Radioactive iodine therapy (RAI) of men treated for thyroid cancer produces a dose-dependent impairment of spermatogenesis and elevation of FSH up to approximately 2 years. Permanent testicular germ cell damage may occur in men treated with high doses of RAI. RAI commonly increases serum concentrations of FSH and LH while reducing inhibin B levels without affecting serum concentrations of testosterone. Thus, radioiodine therapy transiently impairs both germinal and Leydig cell function that usually recover by 18 months posttherapy.

Clinical applications of gonadotropin-releasing hormone and gonadotropin-releasing hormone analogs.

Enhancing Fertility in Mares: Recombinant Equine Gonadotropins.

Advanced reproductive technologies have been developed to enhance fertility in mares and stallions. Some of these technologies in mares include superovulation, embryo transfer (ET), intracytoplasmic sperm injection (ICSI), oocyte transfer (OT), gamete intrafallopian transfer (GIFT), and cloning. Superovulation can provide multiple oocytes for these techniques. This review will focus on how recombinant equine follicle-stimulating hormone (reFSH) and recombinant equine luteinizing hormone (reLH) are important for superovulation and ET and may be useful for ICSI, OT, GIFT, and cloning. Superovulation would increase pregnancy rates in normal and subfertile mares and enhance reproductive efficiency when using semen from subfertile stallions. Superovulation depends on a timely interaction of gonadotropins and gonadal feedback in the mare. Historically, several hormone protocols have been used to manipulate follicular waves to increase development and ovulations in cycling, anestrous, and transitional mares. Attempts to superovulate cyclic mares or induce the first ovulation of the year in anestrous or transitional mares using preparations of equine chorionic gonadotropin, gonadotropin-releasing hormone (GnRH), GnRH agonists, porcine FSH, domperidone, sulpiride, equine pituitary extracts, native equine FSH, human chorionic gonadotropin, progesterone, and immunization against inhibin have produced variable results. The use of recombinant technology has improved the ability to produce a reliable product in substantial quantities that is free of other hormones and possible contaminants. Several studies using reFSH and reLH that demonstrate their efficacy to superovulate the mare and induce the first ovulation of the year will be discussed in this review.

[The treatment of hypogonadism and maintenance of fertility in men].

In past few years we observed the increasing of population of men, who are treated with testosterone due to hypogonadism associated with aging but the most of them have no indications to testosterone replacement therapy. The classical symptoms of hypogonadism including depression, loss of libido, erectile dysfunction, and fatigue may be related to any others diseases. The increase in prevalence of androgenic anabolic steroids specifically among younger athletes is also observed. Exogenous testosterone and anabolic androgenic steroids can inhibit the hypothalamic-pituitary-gonadal axis leading to decreasing of endogenous testosterone synthesis and impaired spermatogenesis. In hypogonadal men who are in reproduction age the goal of therapy should be not only replacement therapy but also achiving and/or maintaining of spermatogenesis. Human chorionic gonadotropin (hCG) and selective estrogens receptor modulators (SERM) are efficacy in treatment of clinical signs and symptoms of hypoigonadism, has been shown to reverse spermatogenesis disturbances and can to maintain elevated intratesticular testosterone levels necessary to optimal spermatogenesis.

Long-acting recombinant human follicle-stimulating hormone (SAFA-FSH) enhances spermatogenesis.

Administration of follicle-stimulating hormone (FSH) has been recommended to stimulate spermatogenesis in infertile men with hypogonadotropic hypogonadism, whose sperm counts do not respond to human chorionic gonadotropin alone. However, FSH has a short serum half-life requiring frequent administration to maintain its therapeutic efficacy. To improve its pharmacokinetic properties, we developed a unique albumin-binder technology, termed "anti-serum albumin Fab-associated" (SAFA) technology. We tested the feasibility of applying SAFA technology to create long-acting FSH as a therapeutic candidate for patients with hypogonadotropic hypogonadism. SAFA-FSH was produced using a Chinese hamster ovary expression system. To confirm the biological function, the production of cyclic AMP and phosphorylation of ERK and CREB were measured in TM4-FSHR cells. The effect of gonadotropin-releasing hormone agonists on spermatogenesis in a hypogonadal rat model was investigated. In in vitro experiments, SAFA-FSH treatment increased the production of cyclic AMP and increased the phosphorylation of ERK and CREB in a dose-dependent manner. In animal experiments, sperm production was not restored by human chorionic gonadotropin treatment alone, but was restored after additional recombinant FSH treatment thrice per week or once every 5 days. Sperm production was restored even after additional SAFA-FSH treatment at intervals of once every 5 or 10 days. Long-acting FSH with bioactivity was successfully created using SAFA technology. These data support further development of SAFA-FSH in a clinical setting, potentially representing an important advancement in the treatment of patients with hypogonadotropic hypogonadism.

Emerging medication for the treatment of male hypogonadism.

Male hypogonadism is characterized by inadequate production of Testosterone (T) (hypoandrogenism) and deficiencies in spermatogenesis. The main treatment of male hypogonadism is T replacement therapy (TRT), but for some of the patients, alternative drugs may be more suitable. The available literature of T and alternative treatments for male hypogonadism are discussed. Transdermal application of T gels are the most commonly used route of T administration. Some oral T formulations are either associated with hepatic toxicity (i.e. methyltestosterone) or short half-lives that require multiple doses per day (i.e. oral testosterone undecanoate). Short acting, injectable T formulations are also available. If the patient prefers not to use daily drugs or short acting injectable formulations, depot formulations such as injectable testosterone undecanoate (TU) may be a good alternative. If the patient has hypogonadotropic hypogonadism and desires fertility or if he is adolescent, instead of TRT, gonadotropins can be started to stimulate testicular growth and spermatogenesis. In obese patients or for the patients having high risks for TRT, off label aromatase inhibitors (AI) and clomiphene citrate (CC), may be considered to stimulate LH, FSH and T levels. In patients with high prostate disease risk, selective androgen receptor modulators may be an alternative treatment but these latter treatments have not had high level evidence.

Studies on human conception.

Effect of rejuvenation hormones on spermatogenesis.

To review the current literature for the effect of hormones used in rejuvenation clinics on the maintenance of spermatogenesis. Review of published literature. Not applicable. Men who have undergone exogenous testosterone (T) and/or anabolic androgenic steroid (AAS) therapies. None. Semen analysis, pregnancy outcomes, and time to recovery of spermatogenesis. Exogenous testosterone and anabolic androgenic steroids suppress intratesticular testosterone production, which may lead to azoospermia or severe oligozoospermia. Therapies that protect spermatogenesis involve human chorionic gonadotropin (hCG) therapy and selective estrogen receptor modulators (SERMs). The studies examining the effect of human growth hormone (HGH) on infertile men are uncontrolled and unconvincing, but they do not appear to negatively impact spermatogenesis. At present, routine use of aromatase inhibitors is not recommended based on a lack of long-term data. The use of hormones for rejuvenation is increasing with the aging of the Baby Boomer population. Men desiring children at a later age may be unaware of the side-effect profile of hormones used at rejuvenation centers. Testosterone and anabolic androgenic steroids have well-established detrimental effects on spermatogenesis, but recovery may be possible with cessation. Clomiphene citrate, human growth hormone (HGH)/insulin-like growth factor-1 (IGF-1), human chorionic gonadotropin (hCG), and aromatase inhibitors do not appear to have significant negative effects on sperm production, but quality data are lacking.

Gonadotropin Treatment for the Male Hypogonadotropic Hypogonadism.

Hypogonadotropic hypogonadism (HH) is caused by a dysfunction in the hypothalamus and/or the pituitary gland and it can be congenital or acquired. This condition is biochemically characterized by low or inappropriately normal gonadotropin levels along with low total testosterone levels. If fertility is not an issue, testosterone therapy is the treatment of choice to induce and maintain secondary sexual characteristics and sexual function. Spermatogenesis is frequently impaired in patients with HH, but usually responsive to hormonal therapy such as gonadotropin therapy or GnRH supplementary/replacement therapy. When gonadotropins are the choice of treatment, conventional therapy includes human chorionic gonadotropin (hCG) along with different FSH formulations: human menopausal gonadotropins (hMG), highly purified urinary FSH preparations (hpFSH) (e.g., urofollitropin) or recombinant FSH (rFSH). The combination of FSH and hCG demonstrated to be associated with better outcomes than single compounds, whereas similar results were obtained with different FSH preparations in male individuals; both regarding the ability to stimulate spermatogenesis and eventually inducing physiology pregnancy. Gonadotropins can be administered either subcutaneously or intramuscularly. The combination therapy with hCG and FSH for a period of 12-24 months was found to promote testicular growth in almost all patients, spermatogenesis in approximately 80% and pregnancy rates in the range of 50%. Gynecomastia is the most common side effect of gonadotropin therapy and is due to hCG stimulation of aromatase causing increased secretion of estradiol. The therapeutic success is higher in patients with post-pubertal HH, in those without previously undescended testes, in patients with higher baseline testicular volume, who underwent repeated cycles of therapy and in patients with higher baseline inhibin B serum concentrations. Reversal of hypogonadism can occur in up to 10% of patients but its physiopathologic mechanism has yet to be elucidated. In conclusion, gonadotropin therapy is effective in promoting puberty and in supporting spermatogenesis onset and preservation in HH patients with either hypothalamic or pituitary conditions.

Current landscape of fertility induction in males with congenital hypogonadotropic hypogonadism.

Congenital hypogonadotropic hypogonadism (CHH) is a rare reproductive disorder caused by deficient secretion or action of gonadotropin-releasing hormone (GnRH) and is a hormonally treatable form of male infertility. Both pulsatile GnRH treatment and combined gonadotropin therapy effectively induce spermatogenesis in 75%-80% of males with CHH, albeit the ejaculate does not usually approach normal semen parameters by WHO criteria. This is in some contrast to the cumulative fertility outcomes in females with CHH on gonadotropin treatment that are indistinguishable from those of reproductively normal females. Emerging data provide insights into early life determinants of male fertility (i.e., minipuberty), and research has identified key predictors of outcomes for fertility-inducing treatment in men with CHH. Such developments provide mounting evidence for tailoring approaches to maximize fertility potential in CHH, although there is no clear consensus to date on the optimal approach to fertility-inducing treatment. This review provides an up-to-date review on the current evidence underpinning therapeutic approaches for inducing spermatogenesis in males with CHH. In the absence of evidence-based clinical guidelines, this synthesis of current evidence provides guidance for clinicians working with males with CHH seeking fertility.

Fertility outcomes in male adults with congenital hypogonadotropic hypogonadism treated during puberty with human chorionic gonadotropin and recombinant follicle stimulating hormone.

Hormone replacement therapy with testosterone for pubertal induction in boys with congenital hypogonadotropic hypogonadism (CHH) achieves virilization but not spermatogenesis. By contrast, human chorionic gonadotropin (hCG) and recombinant follicle stimulating hormone (rFSH) provides both virilization and spermatogenesis. Fertility outcomes of boys treated with recombinant therapy during adolescence have been infrequently described. We report fertility induction and pregnancy outcomes in CHH patients treated with recombinant gonadotropins during puberty. Data of six subjects with CHH (n&#x2009;=&#x2009;3 Kallmann syndrome & n&#x2009;=&#x2009;3 Isolated hypogonadotropic hypogonadism) treated with hCG and FSH for pubertal induction were reviewed. Of these, five underwent subsequent fertility induction while one desired fertility at the end of pubertal induction. Partners of all subjects achieved pregnancies using hCG and rFSH, all with full term live births. All infants were clinically normal. This study provides early evidence of proof of concept of use of gonadotropin induction of puberty being beneficial in subsequent fertility outcome.

Factors affecting spermatogenesis upon gonadotropin-replacement therapy: a meta-analytic study.

A meta-analysis was performed to systematically analyse the results of gonadotropin and GnRH therapy in inducing spermatogenesis in subjects with hypogonadotropic hypogonadism (HHG) and azoospermia. An extensive Medline and Embase search was performed including the following words: 'gonadotropins' or 'GnRH', 'infertility', 'hypogonadotropic', 'hypogonadism' and limited to studies in male humans. Overall, 44 and 16 studies were retrieved for gonadotropin and GnRH therapy, respectively. Of those, 43 and 16 considered the appearance of at least one spermatozoa in semen, whereas 26 and 10 considered sperm concentration upon gonadotropin and GnRH, respectively. The combination of the study results showed an overall success rate of 75% (69-81) and 75% (60-85) in achieving spermatogenesis, with a mean sperm concentration obtained of 5.92 (4.72-7.13) and 4.27 (1.80-6.74) million/mL for gonadotropin and GnRH therapy, respectively. The results upon gonadotropin were significantly worse in studies involving only subjects with a pre-pubertal onset HHG, as compared with studies involving a mixed population of pre- and post-pubertal onset [68% (58-77) vs. 84% (76-89), p&#xa0;=&#xa0;0.011 and 3.37 (2.25-4.49) vs. 12.94 (8.00-17.88) million/mL, p&#xa0;<&#xa0;0.0001; for dichotomous and continuous data, respectively]. A similar effect was observed also upon GnRH. No difference in terms of successful achievement of spermatogenesis and sperm concentration was found for different FSH preparations. Previous use of testosterone replacement therapy (TRT) did not affect the results obtained with gonadotropins. Finally, a higher success rate was found for subjects with lower levels of gonadotropins at the baseline and for those using both human chorionic gonadotropin and FSH. Gonadotropin therapy, even with urinary derivatives, is a suitable option in inducing/restoring fertility in azoospermic HHG subjects. Gonadotropins appear to be more efficacious in subjects with a pure secondary nature (low gonadotropins) and a post-pubertal onset of the disorder, whereas previous TRT does not affect outcome.

Therapeutic benefits of gonadotropins in male hypogonadotropic hypogonadism: a focus on spermatogenesis and fertility.

Male hypogonadotropic hypogonadism is characterized by deficient secretion of luteinizing hormone and follicle-stimulating hormone, leading to low testosterone levels, impaired spermatogenesis, and often infertility. Treatment aims to normalize testosterone and induce spermatogenesis, with gonadotropin therapy as standard. Factors affecting treatment success and optimal duration remain unclear. This single-center retrospective cohort study assessed the outcomes of gonadotropin therapy in men with hypogonadotropic hypogonadism and azoospermia. Men &#x2265; 18 years were included. The primary outcome was the successful induction of spermatogenesis. Data on demographics, treatment regimens, semen parameters, pregnancy outcomes, and side effects were collected. Regression analyses identified factors associated with treatment success. Thirty-five men were included. Spermatogenesis was achieved in 74% of patients, with higher success rates in those receiving combined human chorionic gonadotropin and follicle-stimulating hormone therapy (78%) versus human chorionic gonadotropin monotherapy (33%). Of those producing sperm, 69% upgraded to a higher WHO semen category, with 29% reaching normospermia. The median maximum sperm concentration achieved during treatment was 8.3 million/mL (IQR: 1.9-36.3). A larger baseline testicular volume was associated with a higher success rate of spermatogenesis and a shorter time to pregnancy. Pregnancy was achieved in 68% of patients, with 39% through spontaneous conception. The median time to first spermatogenesis was 7 months and to pregnancy was 21 months. Mild side effects occurred in 16% of patients. Gonadotropin therapy is effective and well tolerated in inducing spermatogenesis and achieving pregnancy in azoospermic men with HH. These findings, based on a contemporary Western cohort, provide updated evidence that supports personalized counseling and underscore the importance of long-term treatment adherence for successful fertility restoration. Some men are infertile because their brain does not produce the hormones needed to make sperm. This condition is called hypogonadotropic hypogonadism. These men often have low testosterone and no sperm in their semen. In this study, we looked at whether hormone treatment could help these men produce sperm and have children. We studied 35 men who were given hormone injections at a Dutch university hospital. After treatment, 74% of them started producing sperm. Those who received a combination of two hormones had better results than those who received only one. Almost 70% of men with sperm had better sperm quality, and over a quarter reached normal sperm levels. Two-thirds of men who wanted children became fathers, mostly through natural conception. Our findings show that hormone treatment is safe and often successful. This can offer hope to men with this condition who want to become fathers.

Efficacy of Non-Testosterone-Based Treatment in Hypogonadal Men: A Review.

Although testosterone replacement therapy is an effective treatment for hypogonadism, there are safety concerns regarding potential cardiovascular risks and fertility preservation. To assess the effect of selective estrogen receptor modulator (SERM), aromatase inhibitor, and human chorionic gonadotropin (hCG) on total testosterone (TT) levels and hypogonadism. We performed a systematic literature review from 1987 to 2019 via PubMed, Cochrane review, and Web of Science. Terms used were infertility, hypogonadism, alternative to testosterone therapy, selective estrogen receptor modulator, aromatase inhibitor, and human chorionic gonadotropin. Studies that reported an effect of TT and hypogonadism after treatment of each medication were selected. Hypogonadal symptoms were assessed by the Androgen Deficiency of The Aging Male (ADAM) questionnaire. Aggregated data were analyzed via Chi-squared analysis. From literature, 25 studies were selected; of which, 12 evaluated efficacy of aromatase inhibitor, 8 evaluated SERMs, and 5 evaluated hCG effects. For SERMs, 512 patients with mean age 42.3&#xa0;&#xb1;&#xa0;1.94&#xa0;years showed mean TT before treatment vs after treatment (167.9&#xa0;&#xb1;&#xa0;202.8 [ng/dl] vs 366.2&#xa0;&#xb1;&#xa0;32.3 [ng/dl], P&#xa0;<&#xa0;.0001 [180.5-216.1 95% confidence interval {CI}]). For aromatase inhibitor, 375 patients with mean age 54.1&#xa0;&#xb1;&#xa0;0.67&#xa0;years showed mean TT before treatment vs after treatment (167.9&#xa0;&#xb1;&#xa0;202.8 [ng/dl] vs 366.2&#xa0;&#xb1;&#xa0;32.3 [ng/dl], P&#xa0;<&#xa0;.0001 [180.5-216.1 95% CI]). SERMs also showed ADAM before treatment vs after treatment (4.95&#xa0;&#xb1;&#xa0;0.28 vs 5.50&#xa0;&#xb1;&#xa0;0.19, P&#xa0;<&#xa0;.0001 [0.523-0.581 95% CI]). For hCG, 196 patients with mean age 41.7&#xa0;&#xb1;&#xa0;1.5&#xa0;years showed mean TT before treatment vs after treatment (284.5&#xa0;&#xb1;&#xa0;13.6 [ng/dl] vs 565.6&#xa0;&#xb1;&#xa0;39.7 [ng/dl], P&#xa0;<&#xa0;.0001 [275.2-287.0 95% CI]). In addition, hCG also showed ADAM before treatment vs after treatment (28.1&#xa0;&#xb1;&#xa0;2.0 vs 30.9&#xa0;&#xb1;&#xa0;2.3, P&#xa0;<&#xa0;.0001 [2.313 95% CI]). Non-testosterone therapies are efficacious in hypogonadal men. Our results show statistically significant improvement in TT and ADAM scores in all 3 medications after treatment. Future studies are warranted to elucidate the relationship between improved hypogonadism and erectile function in the setting of non-testosterone-based treatment. Raheem OA, Chen TT, Le TV, et&#xa0;al. Efficacy of Non-Testosterone-Based Treatment in Hypogonadal Men: A Review. Sex Med Rev 2021;9:381-392.

A clinical algorithm for management of fertility in adolescents with the Klinefelter syndrome.

The review presents a clinical algorithm for the evaluation and treatment for adolescents with Klinefelter's syndrome who desire fertility preservation. Sperm is present in the ejaculate in around 8% of men with Klinefelter's syndrome. Although most are severely oligospermic/azoospermic, 43-45% of men will have sperm found during a testicular sperm extraction, reaching up to 70% in adolescents. Klinefelter's syndrome (47, XXY) causes hypogonadotophic hypogonadism and severe oligospermia/azoospermia rendering natural conception rare. During puberty, boys often require testosterone replacement therapy to develop secondary sexual characteristics, which can further decrease spermatogenesis. There is a progressive decrease of testicular germ cells after the onset of puberty, suggesting that fertility evaluation and preservation should begin shortly thereafter. In adolescents desiring fertility evaluation, any testosterone therapy should be discontinued, hormones and gonadotrophins measured, and a semen analysis obtained. Adolescents with low testosterone are administered aromatase inhibitors, selective estrogen receptors modulators and/or human chorionic gonadotropin to increase endogenous testosterone production. After testosterone levels are normalized, semen analysis is performed, and cryopreservation encouraged if sperm is present. For those without sperm in the ejaculate, a testicular sperm extraction is offered.

Ovarian morphometrics in TP53-deficient mice.

The objective of these investigations was to characterize ovarian responses to hormonal stimulation in TP53-deficient mice. TP53-deficient (KO) and wild-type (WT) mice were induced to ovulate with pregnant mare serum gonadotropin followed by human chorionic gonadotropin. Effect of estradiol on ovarian morphology was determined in induced and control mice implanted with estradiol-containing or placebo pellets. Blood was collected and mice were killed 7 days following implantation. Preserved ovaries were serially sectioned and stained. Numbers of follicles (all classifications) decreased with ovulation induction, but did not differ between WT and KO mice. Numbers of corpora lutea (CL) were less in ovulation-induced KO mice treated with estradiol compared to WT mice. Area of individual CL and serum concentrations of progesterone were greater in ovulation-induced KO mice given estradiol compared to WT mice. Ovulation-induced KO mice had more, larger hemorrhagic follicles than similarly treated WT mice, but hemorrhagic follicles were not influenced by estradiol. Proliferation of ovarian surface epithelial cells did not differ between KO and WT mice induced to ovulate and given estradiol. Ovaries from TP53 gene knockout mice (n = 4) induced to ovulate and given a 21-day estradiol implant three times over 58 days were observed for precursor lesions. There was no indication of precursor lesions in any TP53 KO or WT mouse. TP53 status did not influence recruitment of follicles, but TP53 deficiency hindered the ability of human chorionic gonadotropin to cause ovulation.

Neurotensin: A novel mediator of ovulation?

The midcycle luteinizing hormone (LH) surge initiates a cascade of events within the ovarian follicle which culminates in ovulation. Only mural granulosa cells and theca cells express large numbers of LH receptors, and LH-stimulated paracrine mediators communicate the ovulatory signal within the follicle. Recent reports identified the neuropeptide neurotensin (NTS) as a product of granulosa cells. Here, we demonstrate that granulosa cells were the primary site of NTS expression in macaque ovulatory follicles. Granulosa cell NTS mRNA and protein increased after human chorionic gonadotropin (hCG) administration, which substitutes for the LH surge. To identify ovulatory actions of NTS, a NTS-neutralizing antibody was injected into preovulatory macaque follicles. hCG administration immediately followed, and ovaries were removed 48&#xa0;hours later to evaluate ovulatory events. Follicles injected with control IgG ovulated normally. In contrast, 75% of NTS antibody-injected follicles failed to ovulate, containing oocytes trapped within unruptured, hemorrhagic follicles. Serum progesterone was unchanged. Of the three NTS receptors, SORT1 was highly expressed in follicular granulosa, theca, and endothelial cells; NTSR1 and NTSR2 were expressed at lower levels. Excessive blood cells in NTS antibody-injected follicles indicated vascular anomalies, so the response of monkey ovarian endothelial cells to NTS was evaluated in vitro. NTS stimulated endothelial cell migration and capillary sprout formation, consistent with a role for NTS in vascular remodeling associated with ovulation. In summary, we identified NTS as a possible paracrine mediator of ovulation. Further investigation of the NTS synthesis/response pathway may lead to improved treatments for infertility and novel targets for contraception.

Follicle-stimulating hormone and human spermatogenesis.

The role of follicle-stimulating hormone (FSH) in the control of spermatogenesis is not well established in any species, including man. We studied the effect of an experimentally-induced, selective FSH deficiency on sperm production in normal men. After a 3-mo control period, five normal men received testosterone enanthate (T) 200 mg i. m. weekly to suppress luteinizing hormone (LH) and FSH, until three successive sperm counts revealed azoospermia or severe oligospermia (sperm counts <3 million/ml). Then, while continuing T, human chorionic gonadotropin (hCG) 5,000 IU i. m. three times weekly was administered simultaneously to replace LH activity, leaving FSH activity suppressed. The effect of the selective FSH deficiency produced by hCG plus T administration on sperm production was determined. Sperm counts (performed twice monthly throughout the study) were markedly suppressed during T administration alone (1.0+/-1.0 million/ml mean+/-SE, compared with 106+/-28 million/ml during the control period, P < 0.001). With the addition of hCG to T, sperm counts returned toward normal (46+/-16 million/ml, P < 0.001 compared with T alone). In two subjects, sperm counts during hCG plus T returned into the individual's control range. Sperm motility and morphology were consistently normal in all men during hCG plus T. Serum FSH levels by RIA were normal (110+/-10 ng/ml) in the control period and were suppressed to undetectable levels (<25 ng/ml) in the T alone and hCG plus T periods. Urinary FSH excretion was markedly suppressed in the T alone (60+/-15 mIU/h-2nd IRP, P < 0.01) and hCG plus T (37+/-9 mIU/h, P < 0.01) periods compared with the control period (334+/-78 mIU/h). We conclude that spermatogenesis as assessed by sperm counts, motilities, and morphologies may be reinitiated and maintained at normal levels in men with undetectable blood FSH levels and urinary excretion of FSH less than that of prepubertal children. This conclusion implies that, although FSH may exert effects on human testicular function, maintenance of normal spermatogenesis and reinitiation of sperm production after short-term suppression by exogenous steroids can occur in spite of nearly absent FSH stimulation.

Clomiphene citrate and human chorionic gonadotropin are both effective in restoring testosterone in hypogonadism: a short-course randomized study.

To compare serum testosterone response and symptom improvement in men with hypogonadism in response to treatment with clomiphene citrate (CC), human chorionic gonadotropin (hCG), or a combination of both therapies. A total of 282 men with hypogonadism, wishing to preserve their fertility, were randomized to one of three treatment arms: CC 50&#xa0;mg (n = 95); 5000&#xa0;IU hCG injections twice weekly (n = 94); or a combination of both therapies (CC + hCG; n = 94). All participants had complete medical history and had undergone thorough physical examination, including body mass index (BMI) assessment. Laboratory tests included serum total testosterone and glycated haemoglobin (HbA1c) measurements. Quantitative Androgen Deficiency in the Aging Male (qADAM) questionnaire scores were also recorded. Morning samples of total serum testosterone levels were assessed at three time points: baseline, 1 and 3&#xa0;months. Testosterone levels increased at 1 and 3&#xa0;months in all three groups. The mean baseline testosterone level was 2.31 &#xb1; 0.66&#xa0;nmol/L, BMI was 30.8 &#xb1; 6.2&#xa0;kg/m2 , and qADAM score was 20.5 &#xb1; 3.8. Testosterone levels increased in all&#xa0;groups at all time points, with a final mean value of 5.17 &#xb1; 1.77&#xa0;nmol/L (223% increase) with no statistically significant difference among the groups. qADAM scores had increased in all groups at 1&#xa0;month (CC group: 6.36; hCG group: 5.08; CC + hCG group: 7.26) and at 3&#xa0;months (CC group: 12.73; hCG group: 11.82; CC + hCG group: 15.13) with a significant difference in intergroup analysis for the CC + hCG group compared with the other two groups (P < 0.01). All three treatments were equally effective in restoring testosterone levels. Single-agent CC is simple, cheap and may be used as treatment for hypogonadism when maintenance of fertility is desired. This approach seems to be as effective as either hCG alone or a combination of hCG and CC.

Testosterone supplementation in men: a practical guide for the gynecologist and obstetrician.

Prescribing habits for the treatment of symptomatic hypogonadism have recently stirred controversy surrounding testosterone replacement therapy. As a result, the gynecologist will need to recognize this iatrogenic form of decreased sperm production in couples seeking fertility advice. We have compiled a review of the current literature on testosterone supplementation pertaining to the gynecologic practice. Over the last decade, testosterone use has seen a recent increase including in men desiring to become fathers. Many physicians and hypogonadal men do not recognize that testosterone replacement therapy can have a detrimental effect on spermatogenesis. Fortunately, the cessation of treatment will yield predictable recovery of sperm production for most men. A growing body of evidence supports the use of selective estrogen receptor modulators, such as clomiphene citrate, or human chorionic gonadotropin for the treatment of hypogonadism in men who wish to maintain fertility potential. Recently, the Food and Drug Administration has recommended a labeling update on testosterone products to warn of possible increased risk of venous thromboembolism, cardiovascular events and stroke. Clinicians should be familiar with current practices involving testosterone replacement therapy and the implications on male factor fertility.

Testosterone undecanoate supplementation together with human chorionic gonadotropin does not impair spermatogenesis in males with isolated hypogonadotropic hypogonadism: a retrospective study.

Gonadotropin therapy is commonly used to induce virilization and spermatogenesis in male isolated hypogonadotropic hypogonadism (IHH) patients. In clinical practice, 5.6%-15.0% of male IHH patients show poor responses to gonadotropin treatment; therefore, testosterone (T) supplementation can serve as an alternative therapy to normalize serum T levels and promote virilization. However, treatment with exogenous T impairs spermatogenesis and suppresses intratesticular T levels. This retrospective study aimed to determine whether oral testosterone undecanoate (TU) supplementation together with human chorionic gonadotropin (hCG) would negatively affect spermatogenesis in IHH patients compared with hCG alone. One hundred and seven IHH patients were included in our study. Fifty-four patients received intramuscular hCG and oral TU, and 53 patients received intramuscular hCG alone. The median follow-up time was 29 (range: 12-72) months in both groups. Compared with the hCG group, the hCG/TU group required a shorter median time to normalize serum T levels (P < 0.001) and achieve Tanner stage (III and V) of pubic hair and genital development (P < 0.05). However, there were no significant differences in the rate of seminal spermatozoa appearance, sperm concentration, or median time to achieve different sperm concentration thresholds between the groups. In addition, there were no significant differences in side effects, such as acne and gynecomastia, observed in both groups. This study indicates that oral TU supplementation together with hCG does not impair spermatogenesis in treated IHH patients compared with hCG alone, and it shortens the time to normalize serum T levels and promote virilization.

Hormonal control of spermatogenesis in men: therapeutic aspects in hypogonadotropic hypogonadism.

During the first two trimesters of intrauterine life, fetal sex steroid production is driven by maternal human chorionic gonadotropin (hCG). The HPG axis is activated around the third trimester and remains active for the first 6-months of neonatal life. This so-called mini-puberty is a developmental window that has profound effects on future potential for fertility. In early puberty, GnRH secretion is reactivated first at night and then night and day. Pulsatile GnRH stimulates both LH and FSH, which induce maturation of the seminiferous tubules and Leydig cells. Congenital hypogonadotropic hypogonadism (CHH) results from GnRH deficiency. Men with CHH lack the mini-pubertal and pubertal periods of Sertoli Cell proliferation and thus present with prepubertal testes (<4mL) and low inhibin serum levels --reflecting diminished SC numbers. To induce full maturation of the testes, GnRH-deficient patients can be treated with either pulsatile GnRH, hCG or combined gonadotropin therapy (FSH+hCG). Fertility outcomes with each of these regimens are highly variable. Recently, a randomized, open label treatment study (n=13) addressed the question of whether a sequential treatment with FSH alone prior to LH and FSH (via GnRH pump) could enhance fertility outcomes. All men receiving the sequential treatment developed sperm in the ejaculate, whereas 2/6 men in the other group remained azoospermic. A large, multicenter clinical trial is needed to definitively prove the optimal treatment approach for severe CHH.

Testosterone Replacement Therapy Versus Clomiphene Citrate in the Young Hypogonadal Male.

The use of testosterone to treat hypogonadal symptoms has increased during the past decade. Consequently, one clinical challenge that has arisen is how to approach the young and treatment-na&#xef;ve hypogonadal patient who is still within his reproductive years and may desire children in the future. Testosterone is known to suppress the hypothalamic-pituitary-gonadal axis resulting in suppressed spermatogenesis. There is a concern that, in some men, prolonged testosterone use may result in permanent spermatogenic failure. PATIENT SUMMARY: In this review, we discuss the risks and benefits of available treatment options for the young hypogonadal patient for whom future fertility is an important consideration. Fortunately, alternatives such as clomiphene citrate and human chorionic gonadotropin have been shown to increase endogenous testosterone production. However, their efficacy as treatments for hypogonadal symptoms is still under debate.