Abstract
Androgen receptors are expressed by all stages of growing follicles, and follicular fluid androgen levels are positively correlated to granulosa cell androgen receptor and follicle-stimulating hormone (FSH) receptor expression. Thus, androgens may promote follicular growth, accumulation and/or responsiveness to gonadotropins. This is explored therapeutically in the concept of androgen priming, to improve the ovarian response to stimulation in assisted reproduction. Androgen effects may be achieved in two different ways, either directly by providing exogenous androgen or by providing luteinizing hormone (LH) activity [i.e., LH or human chorionic gonadotropin (hCG)] to stimulate local ovarian production of androgen. The androgen concentrations in follicular fluid by far exceed the levels in female circulation and it has recently been shown that there was no correlation between serum testosterone levels and follicular fluid androgen levels. There is some evidence that administration of exogenous dehydroepiandrosterone or testosterone increases live birth rates, but an optimal protocol has not been established and such adjuvant treatment should be considered experimental. Furthermore, studies exploring long-term administration of LH activity, achieving LH levels comparable to those seen in women with polycystic ovary syndrome, are awaited. The aim of the present review is to discuss critically the most suitable approach for androgen priming from a biological and clinical standpoint, and to evaluate current approaches and results obtained in clinical trials.
Highlights
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
To support the notion that that administration of exogenous androgens acting through the systemic circulation would exert little if any effect on the local intrafollicular environment affecting granulosa cells, it was recently shown that there was no correlation between serum testosterone levels and follicular fluid follicular fluid testosterone, DHEA, estradiol or anti Müllerian Hormone (AMH) concentrations [26]
The treatment regimen was successful in raising intrafollicular androgen levels in pre-ovulatory follicular fluids collected during oocyte retrieval almost 2 weeks after cessation of the priming period, with significantly higher testosterone levels compared to controls [26.4 nmol/l (95%CI 24.6–27.6) vs. 22.4 nmol/l (95%CI 19.3–22.4), p = 0.014] [65]
Summary
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. To support the notion that that administration of exogenous androgens acting through the systemic circulation would exert little if any effect on the local intrafollicular environment affecting granulosa cells, it was recently shown that there was no correlation between serum testosterone levels and follicular fluid follicular fluid testosterone, DHEA, estradiol or anti Müllerian Hormone (AMH) concentrations [26] This confirms that intrafollicular sex-steroid concentrations in individual follicles are unlikely to be affected via the circulation. This group of patients clearly demonstrate that androgen priming with administration of exogenous testosterone in low-responder women may have complex ovarian and systemic effects, and it may be difficult to determine a dose that provides additional recruitment of follicles without inducing unwanted side effects elsewhere in the body. A recent systematic review and meta-analysis of 7 RCTs including women with a poor ovarian response undergoing IVF published from
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