Have you ever found yourself in an argument where you realize that you and the other person aren’t on the same page, but you just can’t seem to get through to each other? It happens between people and it also happens between the body’s organ systems. For example, in type II diabetes, a message (insulin) is being sent, but the cells are resistant to receiving that message. It turns out that a similar issue can arise with the ovaries; even when eggs are present and ovulation is possible, a breakdown in communication can prevent it. However, a 2022 review on addressing infertility in women with primary ovarian insufficiency shows that this communication issue can possibly be resolved, potentially enabling ovulation in women who previously weren’t cycling at all [1].
Even when eggs are present and ovulation is possible, a breakdown in communication can prevent it. However, a 2022 review on addressing infertility in women with primary ovarian insufficiency shows that this communication issue can possibly be resolved, potentially enabling ovulation in women who previously weren’t cycling at all.
FSH desensitization
At the start of each cycle, the pituitary gland in the brain sends a signal, follicle stimulating hormone (FSH), to inform the ovaries that a new group of follicles should prepare for ovulation. Each ovulation requires a group of follicles to work together, and one follicle is selected to release an egg. However, there may be one or more conditions that make it less likely that the ovary will respond, such as autoimmune disease, genetic factors, ovarian damage, a small number of remaining follicles, or unknown factors that impair ovarian function. Loss of ovarian function before age 40 is called primary ovarian insufficiency (POI), also called insuffisance ovarienne prématurée (POF).
So, the pituitary gland is sending its signal, but, for the reasons listed above, the ovaries may not be up to responding. The problem is, the pituitary gland is pas okay with being ignored. At this point the pituitary gland will increase the amount of FSH, the biochemical equivalent to shouting at the ovaries. The poor ovaries, who were just trying their best, do what anyone might do in the face of such beratement; they do their best to tune it out. FSH receptors on the follicles literally move from the outside of the cell to the inside of the cell in order to receive less of the signal (in effect, they become desensitized to it). For the yelling metaphor, this would be like if you could literally pull your ears into your head to stop listening to someone.
Supplemental estrogen: the intermediary that may allow the ovaries to “hear” the pituitary gland
This leads to an unfortunate standoff. The pituitary gland won’t tone down FSH production until the ovaries respond, but the ovaries will refuse to talk with the pituitary gland until it calms the heck down.
With no one willing to compromise, an intermediary is needed: supplemental estrogen.
Normally, when follicles start to develop, they release estrogen. Amongst its other functions, œstrogène lets the pituitary know: “message received.” In this case, supplementing estrogen is like forging an apology note from the ovaries to the pituitary gland to get the pituitary gland to stop overproducing FSH and create a calmer environment where ovulation is more likely to occur.
In fact, that “apology note” might not only calm things down enough to induce ovulation, but also make pregnancy possible! Researchers in a Étude de 2005 indicated that FSH desensitization might also impede implantation, as their study found that women with chronically elevated FSH who receive donor eggs through IVF still have lower chances of successful pregnancy than women with normal FSH levels [2].
Reversing FSH desensitization in clinical trials
In the aforementioned 2022 review exploring how to reverse FSH desensitization, the authors report on a pilot study and a follow-up study that refined their technique. In the pilot study, five women were recruited who had high FSH and low estrogen levels and had not ovulated in over six months. These women were treated with two hormones that would give negative feedback (the “message received!” signal) to the pituitary: estrogen and hMG (human menopausal gonadotropin). With this technique, four out of the five women ovulated and two conceived within five cycles and delivered healthy babies. One of the women who conceived had been diagnosed with POI at age 20 and was receiving treatment 12 years later!
Five women were recruited who had high FSH and low estrogen levels and had not ovulated in over six months. These women were treated with two hormones that would give negative feedback to the pituitary: estrogen and hMG. With this technique, four out of the five women ovulated and two conceived within five cycles and delivered healthy babies.
Even though this study boasted some successful results, a follow-up study to further investigate and refine this FSH-receptor up-regulation technique didn’t take place until 42 years later (which is an unfortunate delay for women who believe that FIV isn’t the answer to infertility and rely on medical research to further a more holistic understanding of their reproductive system). After this study, 100 women were recruited who had not ovulated in a year or more, and the technique was adjusted to be more targeted and cost-effective. Estradiol was used for negative feedback (“message received!” to the pituitary) so that it would be easier to gauge how much estrogen was actually being made by the follicles (this let the researchers see if follicles were maturing and seemed likely to reach ovulation). FSH was supplemented if levels dropped too low, and progestérone was supplemented in the phase lutéale.
The 100 woman follow-up study had lower percentages for ovulation and pregnancy than the five-person study. However (and despite still being a relatively small study), the larger sample size means the follow-up study’s results are likely much more applicable to the average woman experiencing POI. 16% of the time, researchers were able to induce ovulation, and 28% of ovulations in the study resulted in pregnancy. However, half of these pregnancies ended in miscarriage, compared to the estimated 10-25% miscarriage rate experienced by the general population [1]. The article does not discuss why this was the case, but it’s possible that the women in this study, who had not had cycles naturally in over a year, had hormonal abnormalities or reproductive disease beyond what researchers were managing while reversing FSH desensitization.
Cycle charting improves effectiveness of treatment
In summarizing the review, Laura Sullivan notes in an article for FAITS that the women who successfully conceived during this study had been diagnosed with POI an average of 2.2 years before enrolling in the study. For women who did not conceive during the study, they had been diagnosed an average of 4.8 years prior to the study, suggesting that early detection and treatment are key in achieving pregnancy with POI.
Even for the women with a more recent diagnosis, there may have been months or years of cycle abnormalities and overlooked menopause-like symptoms before finally getting answers. Charting can help to identify abnormalities, like absent or unclear peak days or irregular bleeding, early on so women can start treatments at a time when they will be most effective.
Reversing FSH desensitization and hope for the future
Infertility can be a painful and frustrating journey with unexplained symptoms, unknown causes, and more questions than answers. Much of the time, there is no known reason why a woman might develop primary ovarian insufficiency, and the only “treatment” offered for infertility due to POI is FIV. But a few of the women in the FSH desensitization study didn’t just welcome the opportunity to increase their understanding of how the female body works, they welcomed a new family member as a direct result of this research. Hopefully more studies into treating POI (including with other treatment options like stem cells) can allow more women the same opportunity.
Références
[1] Check JH, Choe JK. Maximizing correction of infertility with moderate to marked diminished egg reserve in natural cycles by up-regulating follicle stimulating hormone receptors. Gynecol Reprod Health. 2022;6(4):1-7.
[2] Roberts JE, Spandorfer S, Fasouliotis SJ, Kashyap S, Rosenwaks Z. Taking a basal follicle-stimulating hormone history is essential before initiating in vitro fertilization. Fertil Steril. 2005;83(1):37-41. doi:10.1016/j.fertnstert.2004.06.062
