REVIEW AND COMMENTARY on recent literature in reproductive medicine and biology
The staff of THE REPRODUCTIVE TIMES here offers commentaries on recently published articles, primarily chosen for educational values—in the positive but also in the negative—for clinical purposes, and for their potential translational values to clinical medicine when addressing basic science in reproductive medicine and biology.
NEWS IN GYNECOLOGY
Interesting news on the Polycystic Ovary Syndrome (PCOS) and Endometriosis
HYPERANDROGENISM and PCOS: Here are some new papers about PCOS in general, starting with a worthwhile review article in Endocrine Reviews by Chinese authors which describes the genetic and epigenetic landscape for drug development in PCOS (1).
They correctly point out that all currently available treatments for PCOS are, in principle, only symptomatic and—quite remarkably—not even a single drug has been approved so-far by the FDA specifically for the clinical indication of PCOS. They furthermore again correctly argue that a better understanding of genetics and epigenetics—both increasingly important in new drug developments—therefore may be helpful in the development of PCOS-specific new pharmacological interventions and make this the basic assumption of their review. Since we do not remember a similar angle in any recent PCOS-related article, this is definitely a worthwhile read.
Another in many ways related article in the same issue of Endocrine Reviews offers a history of how causes of common hyperandrogenism were elucidated between 1965 and ca. 2015 (2). The single author of this article is Robert L. Rosenfield, MD, from the Department of Pediatrics and Medicine at the University of Chicago, who was unquestionably one of the most important contributors to the literature during that time period regarding PCOS and hyperandrogenism in general. His opinions were always worth listening to.
Most of our readers by now should be familiar with so-called microRNAs (miRNAs) which are single-stranded, non-coding RNAs which regulate mRNA expression on the post-transcription level. Some observational studies suggested possible involvement of serum microRNAs in PCOS. Austrian investigators now started to expand on these observations by testing serum expression of miR-23a-3p and miR-425-5p in the classical Rotterdam phenotypes of PCOS (A, B, C, D) (3).
As is often the case in PCOS studies, the patient population was quite young (for all patients 27.78 ± 3.69 years). Among individual phenotypes, B was the oldest (mean 25.09 years) and A the youngest (mean 26.42 years) and—interestingly—control patients were the oldest of them all (29.15 ± 3.57 years). This is very important because at least the D phenotype significantly changes with advancing age. At mean age of 27.51 years, it is expected to be in normal androgen range, demonstrate a normal, regular menstrual pattern, and still be normally fertile, as D phenotypes become hypo-androgenic and infertile usually only after approximately age 35 (4).
Unsurprisingly, the D phenotype, however, already had even lower mean DHEA than controls (1.2 vs. 1.37ug/mL), while classical PCOS phenotype A demonstrated the by far highest levels at 23.33 ug/mL. Similarly, the D phenotype also demonstrated the lowest free and total testosterone levels among all PCOS phenotypes, though mildly higher ones than control patients. The study, therefore, does something unfortunately only very few PCOS studies in the literature usually do: it investigated the different phenotypes of PCOS separately, for which it deserves special recognition. Unfortunately, however, the study was underpowered and, therefore, really failed to offer useful new results.
For example, the authors report that the serum expression of miR-23a-3p was upregulated in phenotype B and discriminated it from phenotypes B, C, and D at a significance of P<0.006, but the conclusion was reached on only 10 phenotype As and only 11 Bs, Cs, and Ds, respectively, without apparently controlling for age. The expression of miR-425-5p was downregulated in phenotype C (with only 11 study subjects) and was alleged to discriminate it from the other three phenotypes (again apparently without age adjustments). Likely the one finding of some statistical value was the downregulation of MiR-9305p in all PCOS phenotypes (n=42) versus controls which again only included 8 individuals. In short, a valiant attempt but with very inadequate execution and, therefore, no real progress in our understanding of PCOS.
EXTRACELLULAR VESICLES in PCOS and ENDOMETRIOSIS: And then there is one more review article worth mentioning which addresses a currently very popular subject in medicine in general, so-called extracellular vesicles (ECVs, and their content) which now are reported practically everywhere in the body to have important functions in communicating between cells and have been reported as altered in PCOS and endometriosis. Canadian investigators from Toronto published this review in the Journal of Ovarian Research (5).
ECVs, including exosomes and microvesicles, have been reported in follicular fluid and in tubal fluids. The review included nine PCOS studies, with 2 miRNAs being identified in PCOS, miR-379 and miR-200.
Because of their presence in tubal fluid, they are suspected of playing a role in embryo maturation, as the fertilized egg descends through the tube toward the endometrial cavity while developing to a blastocyst. Because of their suspected impact on embryo growth and development, studies are underway in several laboratories, considering vesicle content for use in in vitro embryo culture.
In the same paper, the authors also look at the effects of extracellular vesicles in endometriosis: Here the paper notes that peritoneal fluid in endometriosis patients contains molecules that modulate the immune response and actually support establishment and maintenance of endometriosis. Having reviewed 11 endometriosis studies, the authors were, however, unable to elucidate any observed patterns common to patients.
And, since we are already addressing endometriosis, some interesting news from the largest cardiology conference in the world (no, this is not a misprint), the European Society of Cardiology (ESC) Congress 2024 in London, UK, where investigators reported that women with endometriosis have a 20% greater risk of heart attacks and strokes than controls (6).
Women of average age 37.3 years were followed for a median of 16 years and a maximum of 45 years. Besides increased risk for myocardial infarctions and ischemic stroke, endometriosis women also demonstrated increased risk for cardiac arrhythmias and heart failure. A prior review article attributed such an association to systemic hormonal, pro-inflammatory, pro-angiogenic, immunologic, and genetic pathways (7). The notion that endometriosis is a systemic rather than localized disease, recently also supported by the research of Yale’s Hugh S. Taylor, MD and collaborators (8), thus appears to be gaining increasing acceptance.
References
1. Chen et al., Endocrine Rev 2024;45(4):437-459
2. Rosenfield RL. Endocrine Rev 2024;45(4):553-592
3. Trummer et al., Int J Mol Sci 2024;25:3205
4. Gleicher et al., Biomedicines 2022;10(7):1505
5. Duval et al. J Ov Res 2024;17:160
6. Havers-Borgersen et al., European Society of Cardiology (ESC) Congress, London, England August 30-September 2, 2024
7. Marchandot et al., Eur Heart J Open 2022;2(1):oeac001 Corrigendum 4(1):oead137
8. Taylor et al., Lancet 2021;397(10276):839-852
How female lifespan relates to early menopause
That women outlive men by on average 5.8 years is well established. The gap has, indeed, grown from 4.8 years in 2010. Now two investigators from Florida, using propensity score matching analysis, investigated sex differences in all-cause mortality and life span between women undergoing premature menopause and men. Propensity scores matching analysis created matched cohorts of women and men using a 1:1 ratio. They then adjusted hazard ratio (HR) values (95% CI) for women and men to survive to the 75th percentile of life span and found them not to be statistically significantly different and there was also no significant difference in the mean life span between deceased women and men in the matched cohorts. In a subgroup analysis, the mean life span also did not differ significantly between deceased women taking hormone therapy and men. Life span of women never using hormone therapy was, however, significantly longer than that of men (78.3 ± 11.6 vs 76.6 ± 11.9 years, P = 0.0154) (1).
These were at various levels interesting results: (i) Life span of women never using hormone therapy was significantly longer than that of men (78.3 ± 11.6 vs 76.6 ± 11.9 years, P = 0.0154), suggesting an adverse effect on female lifespan from hormone therapy. (ii) Women experiencing premature menopause had lower risks of all-cause mortality than men, but the advantage that women had in terms of life span was lost, suggesting that women loose lifespan in association with early menopause..
Reference
1. Xing Z, Kirby R.S. Meonopaus 2024. 31(10):p 887-896
Rapamycin, preventing cyclophosphamide-induced ovarian follicular loss and more
That certain chemotherapies induce abnormal activation and depletion of the pool of primordial follicles in ovaries is well-established. A breakthrough in understanding the process was achieved when it was discovered that cyclophosphamide induced follicle loss by activating the so-called rapamycin (mTOR) pathway, resulting in complete follicle burn out.1 Other investigators then built on this observation and shortly thereafter reported that mTOR inhibitors exhibited a protective effect against such follicle loss,2 a finding several other groups have since confirmed. Now Japanese investigators attempted to elucidate these mechanisms in more detail in a mouse model. Reporting in Human Reproduction,3 they demonstrated that daily administration to mice or rapamycin together with a cyclic regimen of cyclophosphamide (sufficiently potent as a single cancer drug against breast cancer in this model), suppressed cyclophosphamide-induced primordial follicle loss while also demonstrating an inhibitory effect against tumor proliferation. The potential benefits of such an approach in breast cancer patients appear obvious and seem deserving of a clinical trial.
References
1. Adhikari D, Liu K. Cell Cycle 2010;9:1673-1674
2. Goldman et al.; Proc Natl Acad Sci USA 2017;114:3186-3191
3. Tanaka et al., Hum Reprod 2024;39(7):1519-1532
Gender-affirming testosterone treatment effects in trans men on the immune system
Gender-affirming medical care is, of course, currently quite often in the headlines, but usually as a subject of ethical and political interest. In contrast, here are some clinically relevant findings: Females wishing to transition routinely undergo gender-affirming hormone therapy with testosterone (trans men). An interesting study by Swedish investigators now asked the question what this treatment does to their immune system. That this is an important question is obvious, considering the rather profound differences between female and male immune systems, with infectious, inflammatory, and autoimmune conditions, therefore, presenting quite differently between the two sexes.
The investigators longitudinally studied 23 trans men in this study and found that testosterone modulates the immune system through a cross-regulated axis between type-I interferon and tumor necrosis factor. This is, of course, a discovery that is relevant for cis populations as well, as it adds important new knowledge to our understanding of why female and male immune systems differ so significantly (1).
Reference
1. Lakshmikanth et al., Nature 2024;633:155-164
Postmenopausal vulvovaginal symptoms
Interestingly, out of all medical journals, it was the Annals of Internal Medicine which recently dedicated two review papers to what is widely called the genitourinary syndrome of menopause, which includes vulvovaginal complaints (dryness, irritation, pruritus), urinary symptoms (urgency, frequency, dysuria, repeat infections), and symptoms related to sexual intercourse (dyspareunia, poor libido, arousal difficulties, and failure to reach orgasm). Two recent reviews addressed the subject (1,2).
The first systematic review found that most studies in the literature were too small to allow for meaningful results and, therefore, did not offer any meaningful results. The other review suggested that vaginal estrogen, vaginal DHEA, oral ospemifene, and vaginal moisturizers improve some symptoms in the short term, but long-term data are really missing. In short, really not very much evidence that anything really works and a good reason to get proper studies going.
References
1. Ullman et al., Ann Int Med 2024; https://doi.org/10.7326/ANNALS-24-00603; ahead of print.
2. Danan et al., Ann Int Med 2024; https://doi.org/10.7326/ANNALS-24-00610; ahead of print.
A new and innovative ovarian cancer treatment
So-called homologous recombination deficiency (HRD) is frequent in cancers and is a major reason of genomic instability and aneuploidy of cancer cells. It can be found in ca. 50% of ovarian cancers. Investigating over 100 high grade serous ovarian cancer samples, neoadjuvant monotherapy with the PARP inhibitor niraparib achieved impressive response rates.
Effector regulatory T cells (eTregs) were identified as key responders to HRD and neoadjuvant therapies, co-occurring with other T cells reactive to tumor, especially exhausted CD8+ T cells. Moreover, interferon signaling correlated with cancer cells upregulating MHC class II and co-inhibitory ligands, potentially driving Treg and CD8+ cells fates. In a mouse model, depleting eTregs with or without PARP inhibition (a PARP inhibitor is a substance that blocks an enzyme in cells called PARP which helps DNA repair) suppressed tumor growth without toxicity. These findings open the door to eTreg-focused therapied for ovarian cancer as well as other HRD-associated cancers.
Reference
1. Luo et al., Cell 2024;187:4905-4925