CONSIDERING OBESITY AS AN INFERTILITY DIAGNOSIS
Infertility in women and men is widely recognized as a multifactorial condition in which, in many individuals, multiple factors may contribute to the diagnosis. Obesity is in both sexes not only associated with increased infertility but also with poorer outcomes of infertility treatments. Though these associations have been known for decades, most remedies attempting to integrate weight loss into infertility practice have for two reasons failed: Weight loss programs, per se, failed to achieve weight loss goals and/or patients (mostly because of age) did not have the time to pursue weight loss programs over prolonged time periods to effectiveness.
A new family of weight loss drugs, classified as Glucagon-Like Peptide (GLP-1) receptor agonists, has, however, radically changed the picture, virtually guaranteeing significant weight loss within even only three months. This opinion article, therefore, argues that the time has come to consider obesity in both sexes as an infertility diagnosis and include pharmacologic weight loss in obese patients into infertility treatment protocols.
THE ASSOCIATION OF BMI WITH FERTILITY is probably not accidental that the medical literature – and not only the fertility literature – recently appears increasingly interested in how weight loss in women and men can improve fertility. For example, the International Journal of Molecular Sciences recently published a review article on exactly this subject,1 concluding that even modest weight loss can have positive effects on fertility, - though larger weight loss following longer treatment duration, of course, increase these effects. Improvements in female fertility can be observed based on improved hormone profiles, menstrual cyclicity, ovulation rates as well as pregnancy rates. Similarly, men will demonstrate improved hormone profiles, semen analyses, and sexual function. A series of recent articles in Fertility and Sterility also reemphasized the connection between obesity and fertility as well as fertility treatment outcomes, though a well-written accompanying opinion article made the correct point that it would be a mistake to use this information to in any way restrict infertility care to obese patients who need treatment.2
Female infertility: After transfers of 56,564 “euploid” blastocysts, colleagues from Northwestern University in Chicago reported that frozen embryo transfer outcomes declined with increasing female body mass index (BMI).3 Trying to understand why that is, a European group of investigators from a large number of different clinics investigated the effects of BMI in oocyte donors and recipients on IVF cycle outcomes and demonstrated that the donors’ BMI apparently did not matter, while recipients’ obesity affected pregnancy rates adversely in a linear way until BMI 25 kg/m2, when the decline sharply increased up to BMI 35 kg/m2. These findings suggest that obesity, likely, affects establishment of pregnancy through the implantation process; - i.e. the uterus.
This study interestingly also looked at the association between BMI and miscarriage risks and, here, donor as well as recipient BMI positively related to increasing miscarriage risk.4Though donor BMI did not appear to affect pregnancy chances, the authors – in our opinion correctly – nevertheless recommended against using oocyte donors with abnormally high BMI. These data, unsurprisingly, in contrast to above noted pregnancy outcomes, suggest that uterine as well as oocyte influences affect miscarriage risk.
Finally, a group of U.S. investigators used national SART data to investigate the effects of BMI in frozen embryo transfer cycles after PGT-A and reported that a BMI of 23-25 kg/m2 was associated with the highest probability of clinical pregnancy and live birth in autologous as well as donor recipient cycles. That BMIs outside that range were associated with poorer IVF outcomes.5
Male infertility: A recent narrative review in Medicina reviewed the use GLP-1 receptor agonists (for further information, see below). Pointing out that, as already noted above, male obesity can affect fertility in several different ways, including disruption of fertility hormones, poor semen quality, and even technical difficulties during intercourse as well as a known association of erectile dysfunction with obesity.6 The authors suggested that a main effect may lie in the excessive adipose tissue aromatizing testosterone to estradiol; obesity in males, therefore, affects their androgenic hormonal axis by reducing testosterone, thereby indirectly affecting spermatogenesis.
A recent study suggested that weight loss from the GLP-1 analog Liraglutide (Ozempic®) beneficially affected obese men (BMI 30-40 kg/m2) with metabolic hypogonadism and severe erectile dysfunction.7 Whether observed effects were the consequence of weight loss, direct drug effects, or both remains to be established. Because (at least in mice) testes demonstrate GLP-1 receptors on Sertoli and Leydig cells, a direct effect of the medication appears possible. Based on a mouse study, the GLP-1 agonist Exenatide was demonstrated to modulate the brain leptin JAK2/STAT3/SOCS3 pathway in a fat diet-induced obesity and insulin resistance mouse model, 8 improving sperm motility, DNA integrity, and leading to lower expression of pro-inflammatory cytokines.
Whether this new family of weight loss drugs affects medical conditions directly, only through weight loss, or through both, has become a point of discussion in several medical subspecialties since these medications almost daily are revealed to have additional medical benefits, ranging from taming inflammation,9 at least in rodent model improving hyperandrogenism and ovarian function (a potentially promising observation especially for hyperandrogenic obese PCOS patients),10 preventing cardiovascular events,11,12 and improving cardiometabolic parameters.13 They have even been reported to have “mind-body benefits,”14 and cut the craving for opiates.15
GLP-1 AGONISTS (and ANTAGONISTS), THE NEW FAMILY OF WEIGHT LOSS DRUGS
So, what about these new wonder drugs? The first GLP-1 receptor agonist approved by the FDA in June of 2021 was semaglutide.16 Consequently, new anti-obesity drugs like Wegovy,® Ozempic,® and Rybelsus are all semaglutide products. Semaglutide acts as an agonist to the so-called glucagon-like peptide (GLP1) receptor and It, thus, pretends to be the GLP-1 hormone which makes us less hungry by sending signals of feeling full to the brain.
Mounjaro®, a second-generation product, is, however, a little more complicated because it is made up of two effective substances that induce weight loss, - one again a GLP-1 receptor agonist but, now added to it, a so-called glucose-dependent insulinotropic polypeptide (GIP) and, thus mimics the GLP-1 as well as the GIP hormone in their activities on their respective receptors. Like GLP-1, GIP triggers a feeling of fullness.
These compounds, however, likely also affect the brain’s control of food intake and this function has in general been associated with anti-addictive behavior, a reason why these drugs now are also investigated for their potential effectiveness in drug – and other addictive behaviors. Other medications, alleged to be even more effective in inducing weight loss, appear on the way to market. All are destined to change medicine by offering virtually guaranteed weight loss at highly significant proportions to everybody who starts injecting these medications. Remarkably, these medications have relatively few and usually easy to overcome side effects.
CNBC recently reported that Amgen is working hard on “getting in on the booming weight loss drug market,” though with a different approach that works differently from currently available drugs and will require injections, at most, only once a month (in comparison to currently available drugs which require either daily or weekly injections.17 The company, moreover, is also working on an oral weight loss medication. According to this report Goldman Sachs projected that between 10 and 70 million Americans will by 2028 be on these wight loss drugs.
Like already available drugs activate the GLP-1 and GIP receptor, the new Amgen drug allegedly blocks the receptors. The drug was apparently quite successful in a small early-stage phase-one trial, at highest dosage (420mg once a month) diminishing body weight by 14.5% in just 12 weeks.18 Though, as with earlier weight loss drugs in this family the exact reasons why these drugs work so well is still only poorly understood, there is reason to believe that blockage of the receptors may have additional advantages beyond fewer required injections over earlier drugs by maintaining weight loss longer.
The following is a summary from the recent MSNBC article of currently known approved and still experimental weight loss drugs:
ARE GPL-1 DRUGS SAFE?
Since these kinds of medications have already for several years been on the market for the treatment of diabetes, their longer-term profile of side-effects is already quite well known: The most common side-effects are nausea, diarrhea, decreased appetite (if this can be considered a side effect), vomiting, indigestion, and abdominal pain. In a similar pattern to Metformin, these gastro-intestinal symptoms, however, usually quickly disappear with use and these medications are ultimately usually very well tolerated. They, however, should not be used if family members had medullary thyroid carcinoma, Multiple Endocrine Neoplasia syndrome type 2 (MEN 2), or when allergic to individual ingredients in the medicine.
Because some animal models suggested potential abnormalities in newborns as well as small-for- gestational-age offspring, GLP-1 agonists are currently not recommended for use in pregnancy. Nothing is, however, currently known about the human experience with these drugs in pregnancy and drug companies producing them which have announced the establishment of registries for women who, unknowingly, conceived while exposed to GLP-1 agonists, to garner some initial data on whether there, indeed, are effects on mother or offspring from these medications. Companies producing these drugs are, indeed, actively looking for patients who have been taking these medications during pregnancy.
The CHR has started to integrate these medications into cycle preparation protocols for patients with BMI over 30kg/m2 and is maintaining its own registry of patients on these medications. We, however, instructs patients to discontinue the medication at least one month before IVF cycle start. Since these drugs induce slowing of gastric emptying, unsurprisingly, there have been reports of aspirations of gastric content during anesthesia, - yet another reasons why these medications should be discontinued at least one month before IVF cycle start.
How these drugs should be stopped – indeed whether they can ever be stopped without gaining much of the lost weight back – is still unclear. Women, however, of course expect to gain weight during pregnancy. Whether this weight gain will differ after discontinuation of GLP-agonists is also still unknown.
USING THESE DRUGS IN INFERTILITY
It has been known for decades that even rather minor weight loss (by some reports as little a 15 pounds, - by other reports weight loss of only as little as ca. 5% of body weight) already positively affects fertility and improves outcomes of fertility treatments. Those goals in the past were, however, only rarely met, - either because of patient non-compliance with diets and/or exercise routines or because patients, simply, did not have the time to delay their infertility treatments for as long as it may have taken to lose the desired weight before treatment start. These new drugs, however, virtually guarantee significant weight loss within 3, but certainly within 6 months, a time period of delay almost all obese infertility patients can afford.
This does not mean that every female or male infertility patient who is a little overweight should now immediately be treated with these new weight loss drugs. That is most definitely not the case because in milder cases of obesity, as of this point at least, it does not appear that the potential loss in pregnancy chances and/or increases in miscarriage risks warrant the delay of treatment, effort, and (still considerable) cost of these drugs (insurance companies are currently not very forthcoming in covering the significant costs of these medications). But for patients with BMI over 30-35, benefits of weight loss appear worth these negatives; for morbidly obese patients, pretreatment, whether medical or surgical (for example through gastric sleeve surgery) really should be a precondition for fertility treatments, - also because of the potential morbidity of such severe obesity during pregnancy.
Readers who have further questions or comments, please write to arata@thechr.com.
