Androlog of the Fertility and Sterility Dialog

hCG for hypo-hypo men

Started almost 2 years ago

Ive always been confused by how hCG can successfully stimulate spermatogenesis in some hypogonadotropic hypogonadal men.  I get that it should raised leydig cell T production via the LH receptor, but without FSH to stimulate ABP from sertoli cells, how does the T stay in the seminiferous tubules to promotes spermatogenesis?  

From Michael Witt, our Male Reproductive Urologist, "HCG binds to the LH receptor on the Leydig cell which then produces intracellular testosterone that moves into the plasma and into the Sertoli cell. HCG also binds to the Sertoli cell which in combination with intracellular testosterone in the Sertoli cell promotes spermiation." Sincerely Mark P Trolice MD Director, Fertility CARE: The IVF Center Professor, UCF-College of Medicine @drmarktrolice ________________________________

An excellent question. I think the reason this is often difficult to grasp (even for urologists) is that while certain features of the reproductive endocrine system are conserved in both sexes such as estradiol as the primary negative feedback inhibitor for LH, others aren't. Unlike the female, where LH and FSH release are tightly coupled, they are very much not in the male. That's why a male endocrine evaluation absolutely needs both LH and FSH assays: you can't assume the level of one based on the other. So often men, especially those who present later in life, retain a high (often very high) FSH. For those who don't, we prescribe FSH, rFSH, or hMG. With true Kallmann, where the genetic defect affects both LH and FSH, both hCG and FSH/homolog need to be prescribed. Later in adulthood, you have to figure it out and prescribe what's indicated. For a sense of how often you can get away with clomiphene or need to go to hMG, FSH/homolog, or both, see our paper Hussein et al, Optimization of spermatogenesis-regulating hormones in patients with non-obstructive azoospermia and its impact on sperm retrieval: a multicentre study. BJU Int. 2013 Mar;111(3 Pt B):E110-4.

That makes a lot of sense.  Its always fascinated me that the male and female HPG axis work a little differently.  Its context explains this well.

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Just to add a bit more to the conversation, while LH and FSH both affect spermatogenesis, mouse studies show that the presence of LH is critical, and spermatogenesis is still present even in the absence of FSH: " An essential role of LH in driving spermatogenesis in rodents may also be inferred from the findings that mice, in which either FSHβ or the FSH-R have been deleted, are fertile" PMID: 9020850. 

HCG mimics LH, and increases intratesticular T.  HCG monotherapy in hypo-hypo men therefore can work, but as Dr. Nieferberger says, the addition of rFSH may shorten the time to recovery

The point that Dr. Masterson makes is an excellent one. Those foundational biological studies created the rift in how we approach men who are severely hypogonadotropic hypogonadal, e.g. Kallmann. Some prescribe only hCG and see what happens. Some get in front of possible Sertoli cell dysfunction and prescribe hMG, FSH, or rFSH in addition. I fall into the latter, as I'm usually responding to a "time is of the essence" scenario, but I know many whose practice patterns permit a slower treatment algorithm, and it's logical and considered.

Very interesting conversation. Both FSH and LH are required for spermatogenesis. Studies in FSHKO or FSHRKO mice demonstrated that FSH is required to increase the number of spermatogonia and spermatocytes, and without FSH or FSHR the Sertoli cell number is decreased compared to wild type mice (Endocrinology 2008; 149: 3279-85), however FSH alone is unable to promote spermatogenesis beyond the pachytene spermatocites stage, as demonstrated in SCARKO mice (Mol Bio Cell 2020; 31: 2841-2862), so that testosterone is required to proceed beyond meiosis. In addition, FSH and LH have  synergistic effects upon spermatogenesis (e.g. FSH stimulates Androgen Binding Globulin secretion, LH-induced testosterone secretion modulates FSH oligosaccharide complexity and is required to maintain tight junctions between adjacent Sertoli cells).

It is true, as reported by Dr Masterson, that inactivating mutation of FSHR was associated with normal fertility even in men, however  the few men with inactivating mutations in FSH beta subunit reported by literature were completely azoospermic. Further studies clarified that the mutant FSHR is not completely inactive, so that a residual FSH action may be able to promote spermatogenesis (Reprod Sci 2013; 20: 211-33).

Therefore, as wisely pointed out by Dr Niederberger,  HH men need both FSH and hCG treatment.

Hypogonadotrophic Hypogonadal men require both FSH and LH for restoration of Fertility.

Micah has raised a very important question.

HCG, a surrogate for LH, primarily stimulates only Leydig cells and Testosterone production in men. This is useful for development of secondary sexual characteristics. A simpler method of developing secondary sexual characteristics would be administer Testosterone to these patients until fertility is desired. Many of these patients are often identified by Endocrinologists for failure of onset of puberty and often treated with Testosterone to develop secondary sexual characteristics.

Fertility in most of these men with Hypogonadotrophic Hypogonadism can effectively be restored by the administration of HMG. Patients need to be adequately counseled about the need for long term therapy. This may take from 1 to 2 years. In my 45 years experience in the field I have not seen anyone having their Fertility established with HCG alone. Maintenance of  Fertility and spermatogenesis can be achieved with HCG alone. Even there the only reason we use HCG is because it is less expensive. recFSH alone will not establish spermatogenesis. LH is also required for establishment of spermatogenesis and Fertility. 

The ideal treatment for Hypogonadotrophic Hypogonadism is GnRH pulsatile therapy. It is impractical in men and hence it is not practiced. It is still the best practice in women with Hypogonadotrophic Hypogonadism. I  had fairly good experience with that. 

Professor Dr Pandiyan Natarajan,

Chief Consultant in Andrology and Reproductive Sciences,