Almost unbelievable, - the muscle hormone myostatin appears to control the pituitary’s FSH secretion
By Norbert Gleicher, MD, Medical Director and Chief Scientist, at The Center for Human Reproduction in New York City. He can be contacted though The Reproductive Times or directly at either ngleicher@thechr.com or ngleicher@rockefeller.edu.
Briefing: In a first, rather unbelievable discovery, a consortium of Canadian, U.S., and international investigators has just published a bombshell paper in Science magazine, demonstrating that the hypothalamic-pituitary-gonadal axis is not what everybody thought it was. Surprisingly, this paper revealed that a paracrine myokine called myostatin (also known as growth differentiating factor 8, GDF8, and GDF11), which in several species (including humans) has been demonstrated to regulate muscle mass, also acts as a hormone that – in a mouse model – directly affects pituitary follicle-stimulating hormone (FSH) synthesis and, therefore, indirectly affects ovarian function. This kind of FSH-stimulating function had so far exclusively been attributed to other members of the transforming growth factor-β family – so-called activins. These findings are revolutionary because they suggest a previously unknown endocrine axis between muscle and the pituitary gland. They may also imply that increases in muscle mass due to antagonism to myostatin could have adverse consequences on fertility.
If there is one hormone we “fertility experts” have believed we know and understand, it – of course – is follicle-stimulating hormone (FSH). After all, it is what we measure in every one of our patients and it is what we administer to almost all of our patients. But – lo and behold – it now appears that even when it comes to FSH, we still have a lot to learn. A large consortium of investigators has now published a fascinating paper in which they – based on investigations in several mouse models – demonstrated that myostatin, a member of the transforming growth factor-β (TGF-β) superfamily, also known as growth differentiating factor 8 (GDF8), controls FSH secretion by the pituitary (1). Myostatin is produced by skeletal muscle and blocks the muscle cells’ growth and differentiation, which ultimately affects what has been known as the classical endocrine feedback loop of the pituitary, releasing FSH and luteinizing hormone (LH) in response to hypothalamic gonadotropin-releasing hormone (GnRH). These hormones, in turn, act on the female and male gonads to produce steroid and non-steroid hormones, which feedback on the pituitary, thereby inhibiting FSH production. The latter step of inhibition involves the hormone inhibin, which is produced by granulosa cells in females and Sertoli cells in males.
As the paper’s accompanying commentary summarized, the study identified “cross-talk” between peripheral muscle and this basic hormonal feedback loop – a finding with potentially highly important consequences for fertility. Increasing muscle mass may therefore adversely affect fertility (2). Though not mentioned in the paper or commentary, this observation immediately brings to mind the female marathon runner who loses her menstrual pattern – previously widely attributed to her loss of body fat (3). Including the inhibitory function of myostatin on pituitary FSH production, athlete amenorrhea may now need to be viewed as potentially having a multifactorial etiology. Concerns about fertility, of course, are limited to reproductive years.
As the commentary also noted, myostatin levels – like FSH – increase with advancing female age, suggesting that rising myostatin may contribute to rising FSH levels as women get older (2). The authors of the commentary further speculate that antagonists to myostatin may benefit older people by increasing muscle mass, which – again, left unmentioned – has become an increasingly relevant issue due to the explosive growth in the use of GLP-1 agonists for weight loss in both sexes, which, with prolonged use, leads to muscle mass loss (4).
The argument that the hypothalamic-pituitary-gonadal axis in females deserves expansion has been made for many years by CHR investigators, who point out the effect of adrenal androgen production on ovaries and the still unresolved mystery of why adrenal glands – which share an embryonic primordium with ovaries – demonstrate the highest density of anti-Müllerian hormone receptors after ovaries (5). However, that this expansion could involve tissues like skeletal muscle, which has traditionally not been considered part of the reproductive organs, is more than unexpected and opens up new avenues for research. This could redirect our current research emphasis from individual organs to a more comprehensive, whole-body approach.
Moreover, this paper addresses an even more important, though unmentioned, question that has become increasingly apparent in recent years due to so many unexpected developments in science: Why is science still always surprised when it recognizes that what was once considered established biological fact is actually just surface noise in a much more complex physiological system underneath? The reason is simple: Every complex system – whether it is a rocket we plan to send to the moon or Mars, or any biological entity – would not exist if it were dependent on single processes without multiple redundancies.
Because science, until recently, never considered this fact (and one wonders how many scientists to this day publish their discoveries as “isolated” phenomena, as if they were not part of universally multifactorial processes), we used to believe that every gene had only one function, or we considered non-coding DNA to be a useless wasteland; or who cared about microvesicles, which are suddenly seen everywhere performing enormously important functions? And how about what used to be called specks or micro-blobs, now known as biomolecular condensates, reflecting their increasing importance in cell physiology – also now everywhere, and recently the subject of a beautifully illustrated article in Scientific American (6).
The paper discussed here, therefore, may be – perhaps its most important contribution – further evidence for the increasingly obvious notion that the more we know, the less we truly understand! And, in many ways, this – at least for scientists – should be a very exciting conclusion.
References
1. Ongaro et al., Science 2025;387(6731):329-336
2. Steenwinkel T, Pangas SA. Science 2025;387(6731):249-250
3. Chen et al., Ann Transl Med 2023;11(2):132
4. Prado et al., Lancet Diabetes Endocrinol 2024; 12(11):P785-787
5. Gleicher et al., J Clin Endocrinol Metab 2017;10290;3569=3570
6. Ball P. Scientific America. February 2025.; pp 23-27