Androgen Signaling in Uterine Diseases: New Insights and New Targets

Abstract

Common uterine diseases include endometriosis, uterine fibroids, endometrial polyps, endometrial hyperplasia, endometrial cancer, and endometrial dysfunction causing infertility. Patients with uterine diseases often suffer from abdominal pain, menorrhagia, infertility and other symptoms, which seriously impair their health and disturb their lives. Androgens play important roles in the normal physiological functions of the uterus and pathological progress of uterine diseases. Androgens in women are synthesized in the ovaries and adrenal glands. The action of androgens in the uterus is mainly mediated by its ligand androgen receptor (AR) that regulates transcription of the target genes. However, much less is known about the signaling pathways through which androgen functions in uterine diseases, and contradictory findings have been reported. This review summarizes and discusses the progress of research on androgens and the involvement of AR in uterine diseases. Future studies should focus on developing new therapeutic strategies that precisely target specific AR and their related signaling pathways in uterine diseases.

The Role of Obesity in the Etiology and Carcinogenesis of Endometrial Cancer

“…Additionally, normal-weight or underweight women classified on the highest quartile of serum SHBG were less likely to develop EC, the risk being reduced by 61% (OR 0.39, p=0.02) when compared to women in the lowest quartile [ 33 ]. These findings highlight the protective role of SHBG in regulating E bioavailability and potentially reducing EC risk (see Figure 3 ) [ 34 , 35 ].…”

The Role of Obesity in the Etiology and Carcinogenesis of Endometrial Cancer

“…Additionally, normal-weight or underweight women classified on the highest quartile of serum SHBG were less likely to develop EC, the risk being reduced by 61% (OR 0.39, p=0.02) when compared to women in the lowest quartile [ 33 ]. These findings highlight the protective role of SHBG in regulating E bioavailability and potentially reducing EC risk (see Figure 3 ) [ 34 , 35 ].…”

Polymorphism of the FSHB Gene Is Associated with Endometrial Hyperplasia

“…Modern literature data based on a large number of experimental studies indicate a significant effect of androgens (testosterone, dehydroepiandrosterone (DHEA), androstenedione, dihydrotestosterone (DHT)) on the physiology of the female reproductive system [ 8 , 9 ]. These effects of androgens can be independent (due to binding to their specific receptors (AR) and can influence the expression of target genes (for example, targeted genes in the endometrium are CITED2 , ACSS2 , PPFIBP2 , MAOA , etc.…”

“…[ 92 ]) indirectly (due to the effect on estrogens and progesterone), which leads to a complex network of interactions of steroid hormones and plays an important regulatory role in the menstrual cycle, endometrial biology, and follicle development in the ovaries [ 9 ]. In women, 80% of androgens bind to SHBG, 19% bind to serum albumin, and only 1% are free; free androgens are the only active androgens [ 8 ]. In addition, androgens are converted by aromatase into estrogens, and, due to them, they can already realize their biological effects [ 8 ].…”

“…In women, 80% of androgens bind to SHBG, 19% bind to serum albumin, and only 1% are free; free androgens are the only active androgens [ 8 ]. In addition, androgens are converted by aromatase into estrogens, and, due to them, they can already realize their biological effects [ 8 ].…”

A rat model of oral hormonal contraception: Effects on drug preference and gonadal function.

“…However, uterine horn thickness is decreased by the administration of subdermal implants containing LNG; thus, this finding was not so surprising (Hilz et al, 2022). LNG also has a high affinity for androgen receptors; however, treatment with androgen receptor agonists typically stimulate uterine horn growth (Lv et al, 2022). Further, androgen receptors are induced by estradiol in the uterus (Weihua et al, 2002), suggesting that the decreases in uterine horn in our data were mediated by progestin and estrogen mechanisms.…”

The Role of Obesity in the Etiology and Carcinogenesis of Endometrial Cancer

“…Additionally, normal-weight or underweight women classified on the highest quartile of serum SHBG were less likely to develop EC, the risk being reduced by 61% (OR 0.39, p=0.02) when compared to women in the lowest quartile [ 33 ]. These findings highlight the protective role of SHBG in regulating E bioavailability and potentially reducing EC risk (see Figure 3 ) [ 34 , 35 ].…”

Polymorphism of the FSHB Gene Is Associated with Endometrial Hyperplasia

“…Modern literature data based on a large number of experimental studies indicate a significant effect of androgens (testosterone, dehydroepiandrosterone (DHEA), androstenedione, dihydrotestosterone (DHT)) on the physiology of the female reproductive system [ 8 , 9 ]. These effects of androgens can be independent (due to binding to their specific receptors (AR) and can influence the expression of target genes (for example, targeted genes in the endometrium are CITED2 , ACSS2 , PPFIBP2 , MAOA , etc.…”

“…[ 92 ]) indirectly (due to the effect on estrogens and progesterone), which leads to a complex network of interactions of steroid hormones and plays an important regulatory role in the menstrual cycle, endometrial biology, and follicle development in the ovaries [ 9 ]. In women, 80% of androgens bind to SHBG, 19% bind to serum albumin, and only 1% are free; free androgens are the only active androgens [ 8 ]. In addition, androgens are converted by aromatase into estrogens, and, due to them, they can already realize their biological effects [ 8 ].…”

“…In women, 80% of androgens bind to SHBG, 19% bind to serum albumin, and only 1% are free; free androgens are the only active androgens [ 8 ]. In addition, androgens are converted by aromatase into estrogens, and, due to them, they can already realize their biological effects [ 8 ].…”

A rat model of oral hormonal contraception: Effects on drug preference and gonadal function.

“…However, uterine horn thickness is decreased by the administration of subdermal implants containing LNG; thus, this finding was not so surprising (Hilz et al, 2022). LNG also has a high affinity for androgen receptors; however, treatment with androgen receptor agonists typically stimulate uterine horn growth (Lv et al, 2022). Further, androgen receptors are induced by estradiol in the uterus (Weihua et al, 2002), suggesting that the decreases in uterine horn in our data were mediated by progestin and estrogen mechanisms.…”

The Role of Obesity in the Etiology and Carcinogenesis of Endometrial Cancer

“…Additionally, normal-weight or underweight women classified on the highest quartile of serum SHBG were less likely to develop EC, the risk being reduced by 61% (OR 0.39, p=0.02) when compared to women in the lowest quartile [ 33 ]. These findings highlight the protective role of SHBG in regulating E bioavailability and potentially reducing EC risk (see Figure 3 ) [ 34 , 35 ].…”

Polymorphism of the FSHB Gene Is Associated with Endometrial Hyperplasia

“…Modern literature data based on a large number of experimental studies indicate a significant effect of androgens (testosterone, dehydroepiandrosterone (DHEA), androstenedione, dihydrotestosterone (DHT)) on the physiology of the female reproductive system [ 8 , 9 ]. These effects of androgens can be independent (due to binding to their specific receptors (AR) and can influence the expression of target genes (for example, targeted genes in the endometrium are CITED2 , ACSS2 , PPFIBP2 , MAOA , etc.…”

“…[ 92 ]) indirectly (due to the effect on estrogens and progesterone), which leads to a complex network of interactions of steroid hormones and plays an important regulatory role in the menstrual cycle, endometrial biology, and follicle development in the ovaries [ 9 ]. In women, 80% of androgens bind to SHBG, 19% bind to serum albumin, and only 1% are free; free androgens are the only active androgens [ 8 ]. In addition, androgens are converted by aromatase into estrogens, and, due to them, they can already realize their biological effects [ 8 ].…”

“…In women, 80% of androgens bind to SHBG, 19% bind to serum albumin, and only 1% are free; free androgens are the only active androgens [ 8 ]. In addition, androgens are converted by aromatase into estrogens, and, due to them, they can already realize their biological effects [ 8 ].…”

A rat model of oral hormonal contraception: Effects on drug preference and gonadal function.

“…However, uterine horn thickness is decreased by the administration of subdermal implants containing LNG; thus, this finding was not so surprising (Hilz et al, 2022). LNG also has a high affinity for androgen receptors; however, treatment with androgen receptor agonists typically stimulate uterine horn growth (Lv et al, 2022). Further, androgen receptors are induced by estradiol in the uterus (Weihua et al, 2002), suggesting that the decreases in uterine horn in our data were mediated by progestin and estrogen mechanisms.…”