Abstract
BackgroundLow functional ovarian reserve (FOR) is at all ages associated with low testosterone (T) levels. Causes are, however, unknown. We, therefore, investigate whether androgens with low FOR are associated with non-specific immune system activation.Methods322 infertile women with low and normal FOR (controls) were assessed with a broadly based immune profile, which in previous studies has proven effective in differentiating infertile patients with and without immune system activation. Patients were either immune-positive (greater than or equal to one positive tested parameter) or immune negative (no positive test). 135 suffered from prematurely diminished FOR (POA/OPOI; < age 38), 155 from physiologic diminished FOR due to age (DOR; > age 40), and 32 were controls (< age 38 with normal age-specific FOR). Prevalence of immune-positive vs. negative was assessed in all 3 patient groups.ResultsWomen with immune abnormalities, overall, demonstrated higher total T (TT, P = 0.004) and free T (FT, P < 0.001) levels than those without. The three clinical and two immunologic-defined patient groups demonstrated significant statistical interaction in mean TT (P = 0.008), with mean TT and FT in women with positive immune findings being significantly higher in control than in POA/OPOI and physiologic DOR patients (all 4 differences P < 0.001). No such differences between the three groups were seen in women without immune abnormalities.ConclusionsIn this study we used a definition of immune-positivity, which favors sensitivity over specificity, resulting in significant numbers of false-positives but likely only few false-negatives. The study allows suggesting the possibility of an immune system-derived androgen-production factor (APF), which maintains normal androgen levels but is deficient in women with low FOR and immune system inactivity. Existence of such an APF would suggest the presence of a still unknown functional adrenal autoimmune system.
Highlights
Low functional ovarian reserve (FOR) is at all ages associated with low testosterone (T) levels
Study populations This study involved the retrospective investigation of a cohort of 322 infertile women for whom complete data sets were available in the center’s electronic research data bank of The Center for Human Reproduction – New York, a private clinical and research center, specializing in reproductive endocrinology and infertility. They were divided into three distinct groups: (i) 135 Women with premature ovarian aging (POA)/occult primary ovarian insufficiency (OPOI) (Group 1), defined as patients under age 38 years with abnormally elevated age-specific follicle stimulating hormone (FSH) [16] and/or abnormally low age-specific antiMüllerian hormone (AMH) [17]; (ii) 155 Women above age 40 years with age-dependent diminished FOR (DFOR), here described as physiologic Diminished ovarian reserve (DOR) (Group 2); and (iii) 32 control patients, defined as infertility patients under age 38 with normal age-specific FOR, based on FSH and AMH levels
Mean ages were in controls 33.1 ± 3.7 years, in POA/OPOI women 34.5 ± 3.2 and in physiologic DOR, 43.2 ± 2.4 years (Sidak test, controls vs. DOR and POA/OPOI vs. DOR, both P < 0.001; controls vs. POA/OPOI P = 0.04)
Summary
Low functional ovarian reserve (FOR) is at all ages associated with low testosterone (T) levels. Most investigators describe ovarian reserve (OR) as the sum of all remaining follicles This definition, includes in a majority the non-growing pool of primordial follicles, which cannot be reliably assessed [1,2]. Because total primordial follicles appear to correlate to recruited follicles, and because antiMüllerian hormone (AMH) appears representative of small growing follicles (after recruitment), AMH is widely considered the most accurate tool to assess TOR [1,3]. Small growing follicles in mouse studies have been demonstrated dependent on androgen receptor (AR)-mediated effects on granulosa cells [4], which, synergistic with follicle stimulating hormone (FSH), lead to normal follicle growth and oocyte development. Androgen sources are adjacent theca cells in the ovary and the zona reticularis of the adrenals
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