Hypogonadotropic Hypogonadism

Hypogonadotropic Hypogonadism

1. Hypogonadotropic Hypogonadism Eko Indra Pradono

2. Overview of hypogonadism Hypogonadism is characterised by impaired testicular function, which may affect spermatogenesis and/or testosterone synthesis The symptoms of hypogonadism depend on the degree of androgen deficiency The aetiological and pathogenetic mechanisms of male hypogonadism can be divided into 3 main categories :

3. Overview Isolated gonadotropin deficiency or hypogonadotropic hypogonadism (HH) Rare cause of subfertility (1% of male infertility cases) Congenital or acquired Acquired causes : Pituitary disease (prior surgery, infarction, tumors, infection, metabolic conditions ) Most common  anosmic form or Kallman syndrome (1:10,000 and 1:60,000 births)

4. Kallman syndrome (1) Results from failure to secrete GnRH by the hypothalamus  low gonadotropin levels  failure to transition prepubertal testis to postpubertal level of function GnRH deficiency  result of failed embryonic migration of neuroendocrine GnRH cells from olfactory epithelium to forebrain Absence or hypoplasia of olfactory bulbs  concurrent anosmia Kallman syndrome represents genetically diverse group of diseases with: Both X-chromosome linked inheritance via mutation in KAL1 gene Autosomal dominant inheritance via mutations in Fibroblast Growt Factor Reseptor 1 ( FGFR1), FGFR8, Prokineticin Reseptor 2 (PROKR2), PROK2 genes. Mutations in these 5 genes  30% Kallman syndrome patients

5. Kallman syndrome (2) Clinical features:

6. Kallman syndrome (3)

7. PRADER-WILLI SYNDROME (1) Caused by microdeletions or mutations on the paternal chromosome 15 at the q11 or 13 location Because of concurrent medical problems in these patients, most do not seek treatment for infertility Clinical features :

8. PRADER-WILLI SYNDROME (2)

9. DIAGNOSTIC OF HH (1) HH usually presents in the late teenage years when the patient fails to undergo the usual pubertal changes with secondary virilization Important to distinguish HH from constitutional delay of growth and puberty (CGDP) because they share many clinical and hormonal features and yet require markedly different treatments

10. DIAGNOSTIC OF HH (2) Number of physiologic and stimulatory tests to discriminate : Serial serum LH measurements Prolactin response to THR and GnRH HCG stimulation tests

11. DIAGNOSTIC OF HH (3) A suspected tumour requires imaging [computed tomography (CT) or magnetic resonance imaging (MRI)] of the sella region and a complete endocrine work-up Normal androgen levels and subsequent development of secondary sex characteristics (in cases of onset of hypogonadism before puberty) and a eugonadal state can be achieved by androgen replacement alone

12. Goals of HH treatment

13. Treatments of hh (1) Various effective methods of testosterone replacement therapy Adequacy of replacement can be assessed by: Serum testosterone levels (within midrange of normal) Observation of desired phenotypic response to therapy

14. EAU RECOMMENDATIONS Recommendations Strength rating Provide testosterone replacement therapy for symptomatic patients with primary and secondary hypogonadism who are not considering parenthood. Strong In men with hypogonadotropic hypogonadism, induce spermatogenesis by an effective drug therapy ( human chorionic gonadotropin, human menopausal gonadotropins, recombinant follicle-stimulating hormone, highly purified FSH ). Strong Do not use testosterone replacement for the treatment of male infertility. Strong

15. Treatments of hh (1) h uman Chorionic Gonadotropin ( hCG ) as First -line therapy : subcutaneously at a dose of 1500 to 2000 IU two to three times per week, for 4 to 6 months. Without significant further improvement, FSH stimulation is added to the treatment regimen to induce spermatogenesis

16. Treatments of hh (2) FSH (administed as human menopausal gonadotropin/hMG ) Contains both FSH & LH in equal dose or with recombinant human FSH formulation at a dose of 75 IU, 2-3x/week and recombinant FSH at a dose of 37.5 -75 IU, 2-3x/ weeks continued until attainment of sperm concentrations of at least 5 million per mL in the ejaculate or pregnancy C lomiphene (antiestrogen) or tamoxifen or with aromatase inhibitors such as anastrozole or letrozole restore testosterone levels and possibly improve spermatogenesis in selected patients with HH presenting after puberty with intact pituitary function initial dose 25 mg every day or 50 mg every other day and is increased by titrating to serum testosterone to a maximum of 100 mg daily

17. Treatments of hh (3) In some studies, the titration target is restoration of normal androgen levels; in others, it is elevated at 600 to 800 ng/dL The typical dose of anastrozole is 1 mg daily

18. TREATMENT OUTCOME & CONSIDERATIONS The vast majority of patients will be able to conceive after gonadotropin therapy, although 71% of the patients with subsequent fertility have sperm concentrations considerably lower than normal, suggesting that these patients are often able to conceive with low counts 10% of patients may maintain normal serum testosterone levels after cessation of all endocrine therapy, implying that HH may be reversible in some patients In patients who have developed hypogonadism before puberty and have not been treated with gonadotropins or GnRH  may be need one to two years of therapy to achieve sperm production

19. HH MEdications Menopur : Menotropin / human M enopausal G onadotropin ( hMG ) 225 IU FSH & 225 IU LH @75 IU, SC 2-3x/week, until attainment of sperm concentration (at least 5 million/ml) or pegnancy is obtained Roburantia Starfer / Torrex : Zink, Folic Acid, Ascorbic acid, cyanocobalamin , sodium selenium, fructose, arginine, carnitine , Vit E

20. REFERENCES Jungwirth A, Diemer T, Kopa Z, Krausz C, Minhas S, Tournaye H. Male infertility. EAU Guidelines 2019. Niederberger CS. Chapter 24: Male infertility. In: Kavoussi LR, Partin AW, Peters CA. Campbell- walsh Urology. 11 th ed. Philadelphia: Elsevier, Inc.;2016.

21. Disorder associated w/ male hypogonadism