The follicular hormonal profile in low-responder patients undergoing unstimulated cycles: is it hypoandrogenic?

Abstract

The present project has been supported by the R+D programme from the Generalitat Valenciana (Regional Valencian Government) IMPIVA MIDTF/2010/95. The authors have no conflict of interest to declare.

The hormonal composition of follicular fluid and its implications for ovarian cancer pathogenesis

“…As the follicle develops, granulosa cells produce large polysaccharides, hormones, and growth factors which cannot pass the 100 kDA follicle-blood barrier, causing an osmotic gradient which further increases FF volume [19,20]. Ultimately, mature follicles in unstimulated women can contain as much as 1,000 fold higher levels of estrogen and progesterone than the serum, whereas other hormones such as follicle stimulating hormone (FSH) are not differentially concentrated [21]. Other potentially harmful factors, such as reactive oxygen species (ROS), have a physiologic window; their presence is required for embryo formation but particularly high levels within the FF are associated with poor embryo formation in IVF patients [22].…”

“…With regards to cancer, estradiol is also thought to have a mutagenic effect, particularly in female reproductive tissue where elevated blood levels of estrogens have been associated with an increased risk of breast and uterine cancer [30,31]. Since follicular fluid E2 concentrations can reach 1000 fold that of serum levels, estradiol may also play a role in HGSOC pathogenesis [21]. The two main oncogenic mechanisms proposed for estrogen are indirect stimulation of cell growth, leading to an increased risk of transcriptional errors, and direct generation of DNA damage, particularly through the production of free-radicals [32].…”

“…Studies measuring hormone levels in women who required large amounts of stimulation to ovulate and control subjects undergoing unstimulated In Vitro Fertilization (IVF) found that while older age decreased FF E2 levels, young low responders were comparable to control donors [21]. Further studies measuring FF E2 levels in women undergoing standard IVF with low ovarian reserve confirmed that FF E2 levels decrease with age, but are higher in younger women with low ovarian reserve compared to control donors [35].…”

Exploratory study of the association of steroid profiles in stimulated ovarian follicular fluid with outcomes of IVF treatment

“…In earlier published studies [10,13,45,43,9,30] measurements of steroids in FF were performed using Immunoassays (IAs), which were shown to suffer from cross-reactivity with structurallyrelated compounds [41,42,19,22] or using gas chromatography mass spectrometry methods, which are more specific [3,8,6,38,7]. Advancements in biological mass spectrometry helped to overcome many of the pitfalls associated with IAs and enabled high specificity simultaneous accurate quantification of multiple steroids [17,23,24,[18][19][20][21][22]25].…”

Response: poor responders and androgen adjuvant treatment: “still haven't found what I'm looking for…”

“…Using an in-vitro model of cultured luteinized granulosa cells, we observed a time-and dose-dependent increase in FSH receptor expression when these cells were treated with testosterone (Garcia-Velasco et al, 2012). However, when we prospectively evaluated serum and follicular fluid androstendione and testosterone in low responder women, both young (≤35 years) and older (>35 years), we could not find any difference in their hormonal milieu when compared to control women (de los Santos et al, 2013).…”