Abstract:Androgen production by the ovary is an essential requirement for normal cyclical secretion of estradiol but its physiological role extends to important actions on both preantral and antral follicle development, including promotion of granulosa cell proliferation. It is likely only in mature antral follicles that androgens encourage apoptosis and consequent follicle atresia, and this may be an important mechanism to ensure mono-follicular ovulation in primates, including humans. Recent studies have provided new… Show more
“…In the human, this occurs when follicles are between 4 and 6 mm in diameter (Gougeon class 5 to 6). As will be discussed, the transition from peak androgen dependence also occurs around this same time [ 18 , 24 ]. Fig.…”
Section: Introductionmentioning
confidence: 99%
“…Although androgens are critical hormones in the pre-antral to early antral follicle’s stage of development, they are not acting alone in promoting follicle growth and development. For example, acting in conjunction with FSH and modulated by IGF-1 and GDF9 (positively) and AMH and BMP15 (negatively), androgens promote granulosa cell proliferation [ 24 ] (Fig. 4 ).…”
Section: Introductionmentioning
confidence: 99%
“…More granulosa cells in a follicle lead to more FSH receptors per follicle with increased estrogen production resulting in more mitosis [ 27 , 33 ]. Estrogen is also essential for LH receptor expression in the granulosa cell, which only starts to be expressed on granulosa cells in an antral follicle greater than 10 mm in diameter and is required for eventual ovulation [ 24 ].…”
Letrozole is a targeted aromatase inhibitor which has primarily been used in post-menopausal women with breast cancer. Recently, it has been utilized in infertile pre-menopausal women because of its ability to enhance FSH production for ovulation induction. However, the ovarian follicle’s response to FSH is only a part of the endocrine events occurring in a developing follicle. The health of the small antral follicles is driven primarily by androgens, which contribute to granulosa cell mitosis, sensitivity to FSH, and resistance to atresia. In contrast, elevated androgens in the late antral to pre-ovulatory follicle have a negative impact on follicle health and lead to atresia and cystic follicle formation. This ovarian physiologic data suggests that current applications of letrozole to infertility may be squandering some of the primary benefits available in using letrozole to promote follicle development. Four applications of letrozole to infertility that have appeared in the medical literature are reviewed. Androgen-related benefits are reviewed and various questions put forward about how letrozole could be more effectively used to help patients in these settings.
“…In the human, this occurs when follicles are between 4 and 6 mm in diameter (Gougeon class 5 to 6). As will be discussed, the transition from peak androgen dependence also occurs around this same time [ 18 , 24 ]. Fig.…”
Section: Introductionmentioning
confidence: 99%
“…Although androgens are critical hormones in the pre-antral to early antral follicle’s stage of development, they are not acting alone in promoting follicle growth and development. For example, acting in conjunction with FSH and modulated by IGF-1 and GDF9 (positively) and AMH and BMP15 (negatively), androgens promote granulosa cell proliferation [ 24 ] (Fig. 4 ).…”
Section: Introductionmentioning
confidence: 99%
“…More granulosa cells in a follicle lead to more FSH receptors per follicle with increased estrogen production resulting in more mitosis [ 27 , 33 ]. Estrogen is also essential for LH receptor expression in the granulosa cell, which only starts to be expressed on granulosa cells in an antral follicle greater than 10 mm in diameter and is required for eventual ovulation [ 24 ].…”
Letrozole is a targeted aromatase inhibitor which has primarily been used in post-menopausal women with breast cancer. Recently, it has been utilized in infertile pre-menopausal women because of its ability to enhance FSH production for ovulation induction. However, the ovarian follicle’s response to FSH is only a part of the endocrine events occurring in a developing follicle. The health of the small antral follicles is driven primarily by androgens, which contribute to granulosa cell mitosis, sensitivity to FSH, and resistance to atresia. In contrast, elevated androgens in the late antral to pre-ovulatory follicle have a negative impact on follicle health and lead to atresia and cystic follicle formation. This ovarian physiologic data suggests that current applications of letrozole to infertility may be squandering some of the primary benefits available in using letrozole to promote follicle development. Four applications of letrozole to infertility that have appeared in the medical literature are reviewed. Androgen-related benefits are reviewed and various questions put forward about how letrozole could be more effectively used to help patients in these settings.
“…Androgens play key roles in a range of reproductive functions necessary for conception, acting directly through the androgen receptor (AR), or as necessary precursors for estrogen synthesis. Androgens are considered to represent a double-edged sword in human follicular development, with positive effects on follicles at preantral and small antral stages and potential negative effects on pre-ovulatory follicles unless appropriate downregulation of granulosa cell AR takes place (1,2). Women with polycystic ovary syndrome (PCOS) are characterized by a high antral follicle count and increased androgen levels, and androgens seem to play an important role in aberrant follicle development and anovulation in this group of women (3,4).…”
Androgen priming has a biological basis for improving poor response during ovarian stimulation. While administration of exogenous androgens may have effects on early stages of follicle development, they are unlikely to affect the androgen concentrations in more mature follicles. Conversely, administration of hormones that increases the intra-follicular androgen concentration may have effects across a broader range of stage of follicle development.
“…Women with PCOS experience higher rates of pregnancy loss compared to non-PCOS women in populations seeking infertility therapy [4], which may be related to poor oocyte quality due to impaired folliculogenesis [5,6]. Studies on nonprimate [7] and primate species [8,9] identified stage-specific effects of excess androgen on follicular development and function. In vitro studies employing three-dimensional culture of macaque follicles suggest that androgen actions are critical for pre-antral folliculogenesis in primates, but once follicles reach the antral stage, continued exposure to elevated androgens results in smaller antral follicles producing less local factors (VEGF, AMH) and steroid (estradiol, E2) compared to controls [9].…”
Purpose To investigate the impact of chronically elevated androgens in the presence and absence of an obesogenic diet on oocyte quality in the naturally selected primate periovulatory follicle. Methods Rhesus macaques were treated using a 2-by-2 factorial design (n = 10/treatment) near the onset of menarche with implants containing either cholesterol (C) or testosterone (T, 4-5-fold increase above C) and a standard or BWestern-styled iet alone (WSD) or in combination (T+WSD). Following~3.5 years of treatment, females underwent controlled ovulation (COv, n = 7-10/treatment) cycles, and contents of the naturally selected periovulatory follicle were aspirated. Follicular fluid (FF) was analyzed for cytokines, chemokines, growth factors, and steroids. RNA was extracted from luteinizing granulosa cells (LGCs) and assessed by RNA-seq. Results Only healthy, metaphase (M) I/II-stage oocytes (100%) were retrieved in the C group, whereas several degenerated oocytes were recovered in other groups (33-43% of T, WSD, and T+WSD samples). Levels of two chemokines and one growth factor were reduced (p < 0.04) in FF of follicles with a MI/MII oocyte in WSD+T (CCL11) or T and WSD+T groups (CCL2 and FGF2) compared to C and/or WSD. Intrafollicular cortisol was elevated in T compared to C follicles (p < 0.02). Changes in the expression pattern of 640+ gene products were detected in LGC samples from follicles with degenerated versus MI/MII-stage oocytes. Pathway analysis on RNAs altered by T and/or WSD found enrichment of genes mapping to steroidogenic and immune cell pathways. Conclusions Female primates experiencing hyperandrogenemia and/or consuming a WSD exhibit an altered intrafollicular microenvironment and reduced oocyte quality/competency, despite displaying menstrual cyclicity.
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