The Role of Central Androgen Receptor Actions in Regulating the Hypothalamic-Pituitary-Ovarian Axis.

Published on Jan 1, 2018in Neuroendocrinology4.271
· DOI :10.1159/000487762
Kirsty A Walters24
Estimated H-index: 24
,
Melissa C Edwards5
Estimated H-index: 5
+ 4 AuthorsDavid J. Handelsman104
Estimated H-index: 104
Sources
Abstract
The androgen receptor (AR) is expressed throughout the hypothalamic-pituitary-gonadal (HPG) axis, and findings from female global AR knockout mice confirm that AR-mediated androgen actions play important roles in regulating female reproductive function. We generated neuron-specific AR knockout mice (NeurARKO) to investigate the functional role of neuronal AR-mediated androgen action in regulating the female HPG axis and fertility. Relative to control females, NeurARKO females exhibited elevated luteinizing hormone (LH) levels at diestrus ( p p Kiss1 mRNA expression in the anteroventral periventricular nucleus at diestrus ( p p Kiss1 ( p Tac2 , p p p < 0.01). Despite the findings of aberrant neuroendocrine and ovarian characteristics in the NeurARKO females, estrous cyclicity and overall fertility were comparable between NeurARKO and WT females. In conclusion, our findings revealed that selective loss of neuronal AR actions impacts the kisspeptin/GnRH/LH cascade leading to compromised ovarian follicle dynamics.
📖 Papers frequently viewed together
33 Citations
10 Authors (Yaping Ma, ..., Sheng Wu)
35 Citations
138 Citations
References51
Newest
#1Brian P. Kenealy (UW: University of Wisconsin-Madison)H-Index: 12
#2Kim L. Keen (UW: University of Wisconsin-Madison)H-Index: 23
Last. Ei Terasawa (UW: University of Wisconsin-Madison)H-Index: 59
view all 5 authors...
Abstract Negative and positive feedback effects of ovarian 17β-estradiol (E2) regulating release of gonadotropin releasing hormone (GnRH) and luteinizing hormone (LH) are pivotal events in female reproductive function. While ovarian feedback on hypothalamo–pituitary function is a well-established concept, the present study shows that neuroestradiol, locally synthesized in the hypothalamus, is a part of estrogen’s positive feedback loop. In experiment 1, E2 benzoate-induced LH surges in ovariecto...
15 CitationsSource
#1Rachel A Davey (University of Melbourne)H-Index: 25
#2Michele V Clarke (University of Melbourne)H-Index: 9
Last. Jeffrey D Zajac (University of Melbourne)H-Index: 58
view all 10 authors...
: Although it is well established that exogenous androgens have anabolic effects on skeletal muscle mass in humans and mice, data from muscle-specific androgen receptor (AR) knockout (ARKO) mice indicate that myocytic expression of the AR is dispensable for hind-limb muscle mass accrual in males. To identify possible indirect actions of androgens via the AR in neurons to regulate muscle, we generated neuron-ARKO mice in which the dominant DNA binding-dependent actions of the AR are deleted in ne...
16 CitationsSource
#1Kirsty A Walters (UNSW: University of New South Wales)H-Index: 24
#2David J. Handelsman (USYD: University of Sydney)H-Index: 104
Abstract It has been well established for decades that androgens, namely testosterone (T) plays an important role in female reproductive physiology as the precursor for oestradiol (E2). However, in the last decade a direct role for androgens, acting via the androgen receptor (AR), in female reproductive function has been confirmed. Deciphering the specific roles of androgens in ovarian function has been hindered as complete androgen resistant females cannot be generated by natural breeding. In a...
29 CitationsSource
#1Aimee S L Caldwell (USYD: University of Sydney)H-Index: 5
#2Melissa C Edwards (UNSW: University of New South Wales)H-Index: 5
Last. Kirsty A Walters (UNSW: University of New South Wales)H-Index: 24
view all 7 authors...
Polycystic ovary syndrome (PCOS) is a complex hormonal disorder characterized by reproductive, endocrine, and metabolic abnormalities. As the origins of PCOS remain unknown, mechanism-based treatments are not feasible and current management relies on treatment of symptoms. Hyperandrogenism is the most consistent PCOS characteristic; however, it is unclear whether androgen excess, which is treatable, is a cause or a consequence of PCOS. As androgens mediate their actions via the androgen receptor...
87 CitationsSource
#1Yaping MaH-Index: 3
#2Stanley AndrisseH-Index: 4
Last. Sheng Wu (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 18
view all 10 authors...
Androgen and its receptor (AR) plays a critical role in reproductive function, under both physiological and pathophysiological conditions. Female AR global knockout mice are sub-fertile due to both neuroendocrine and ovarian defects. Female offspring from prenatally androgenized heterozygous AR pregnant mice showed rescued estrous cyclicity and fertility. Ar is expressed in granulosa cells, theca interstitial cells, and oocytes in the ovary. We created mice with theca-specific deletion of Ar (Th...
35 CitationsSource
#1Cassandra Yap (UWA: University of Western Australia)H-Index: 4
#2Michaela D Wharfe (UWA: University of Western Australia)H-Index: 7
Last. Jeremy Troy Smith (UWA: University of Western Australia)H-Index: 48
view all 5 authors...
Kisspeptin, the neuropeptide product of the Kiss1 gene, is critical in driving the hypothalamic-pituitary-gonadal (HPG) axis. Kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (Arc) of the hypothalamus mediate differential effects, with the Arc regulating negative feedback of sex steroids and the AVPV regulating positive feedback, vital for the preovulatory surge and gated under circadian control. We aimed to characterize hypothalamic Kiss1 and Kiss1r mRN...
6 CitationsSource
#1Shannon B. Z. Stephens (UCSD: University of California, San Diego)H-Index: 10
#2Kristen P. Tolson (UCSD: University of California, San Diego)H-Index: 12
Last. Alexander S. Kauffman (UCSD: University of California, San Diego)H-Index: 37
view all 7 authors...
Kisspeptin, encoded by Kiss1, stimulates GnRH neurons to govern reproduction. In rodents, estrogen-sensitive kisspeptin neurons in the anterior ventral periventricular nucleus and neighboring periventricular nucleus are thought to mediate sex steroid-induced positive feedback induction of the preovulatory LH surge. These kisspeptin neurons coexpress estrogen and progesterone receptors and display enhanced neuronal activation during the LH surge. However, although estrogen regulation of kisspepti...
61 CitationsSource
#1Kirsty A Walters (USYD: University of Sydney)H-Index: 24
Androgens mediate their actions via the androgen receptor (AR), a member of the nuclear receptor superfamily. AR-mediated androgen action is essential in male reproductive development and function; however, only in the last decade has the suspected but unproven role for AR-mediated actions in female reproduction been firmly established. Deciphering the specific roles and precise pathways by which AR-mediated actions regulate ovarian function has been hindered by confusion on how to interpret res...
74 CitationsSource
#1A.S.L. Caldwell (UWA: University of Western Australia)H-Index: 1
#1Aimee S L Caldwell (USYD: University of Sydney)H-Index: 5
Last. Kirsty A Walters (USYD: University of Sydney)H-Index: 24
view all 10 authors...
Polycystic ovary syndrome (PCOS) is associated with reproductive, endocrine, and metabolic abnormalities. Because hyperandrogenism is the most consistent PCOS feature, we used wild-type (WT) and androgen receptor (AR) knockout (ARKO) mice, together with a mouse model of PCOS, to investigate the contribution of genomic AR-mediated actions in the development of PCOS traits. PCOS features were induced by prenatal exposure to dihydrotestosterone (250 μg) or oil vehicle (control) on days 16–18 of ges...
48 CitationsSource
#1Sheng Wu (Johns Hopkins University)H-Index: 27
#1Sheng Wu (Johns Hopkins University)H-Index: 18
Last. Andrew Wolfe (Johns Hopkins University)H-Index: 33
view all 7 authors...
Polycystic ovary syndrome is the major cause of infertility in reproductive aged women. Polycystic ovary syndrome is associated with high circulating levels of androgens and impaired metabolic function. The goal of this study was to understand how androgen signaling via the androgen receptor (AR) affects reproductive function. We knocked out the AR gene specifically in pituitary gonadotropes (PitARKO) to explore the role of androgen on the development of reproductive function in female mice. The...
33 CitationsSource
Cited By19
Newest
#1Amanda G. Gibson (UM: University of Michigan)
#2Jennifer Jaime (UM: University of Michigan)
Last. Suzanne M. MoenterH-Index: 28
view all 4 authors...
Neuroendocrine control of reproduction is disrupted in many individuals with polycystic ovary syndrome, who present with increased luteinizing hormone (LH), and presumably gonadotropin-releasing hormone (GnRH), release frequency, and high androgen levels. Prenatal androgenization (PNA) recapitulates these phenotypes in primates and rodents. Female offspring of mice injected with dihydrotestosterone (DHT) on gestational D16-18 exhibit disrupted estrous cyclicity, increased LH and testosterone, an...
Source
#2Matan Golan (Agricultural Research Organization, Volcani Center)H-Index: 1
From mammals to fish, reproduction is driven by luteinizing hormone (LH) and follicle-stimulating hormone (FSH) temporally secreted from the pituitary gland. Teleost fish are an excellent model for addressing the unique regulation and function of each gonadotropin cell since, unlike mammals, they synthesize and secrete LH and FSH from distinct cells. Only very distant vertebrate classes (such as fish and birds) demonstrate the mono-hormonal strategy, suggesting a potential convergent evolution. ...
Source
#1Irene E Sucquart (UNSW: University of New South Wales)
#2Ruchi Nagarkar (UNSW: University of New South Wales)
Last. Kirsty A Walters (UNSW: University of New South Wales)H-Index: 24
view all 13 authors...
Polycystic ovary syndrome (PCOS) is a prevalent endocrine condition characterised by a range of endocrine, reproductive and metabolic abnormalities. At present, management of women with PCOS is suboptimal as treatment is only symptomatic. Clinical and experimental advances in our understanding of PCOS etiology support a pivotal role for androgen neuroendocrine actions in PCOS pathogenesis. Hyperandrogenism is a key PCOS trait and androgen actions play a role in regulating the kisspeptin-/neuroki...
2 CitationsSource
Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disease. PCOS patients are characterized by hyperandrogenemia, anovulation, and metabolic dysfunction. Hypothalamus-pituitary-ovary axis imbalance is considered as an important pathophysiology underlying PCOS, indicating that central modulation, especially the abnormal activation of hypothalamic GnRH neurons plays a vital role in PCOS development. Increased GnRH pulse frequency can promote LH secretion, leading to ovarian dysfun...
Source
The management of patients with diminished ovarian reserve (DOR) remains one of the most challenging tasks in IVF clinical practice. Despite the promising results obtained from animal studies regarding the importance of androgens on folliculogenesis, the evidence obtained from clinical studies remains inconclusive. This is mainly due to the lack of an evidence-based methodology applied in the available trials and to the heterogeneity in the inclusion criteria and IVF treatment protocols. In this...
Source
#1Leonardo Bontempi (NIDA: National Institute on Drug Abuse)H-Index: 1
#2Antonello BonciH-Index: 87
Anabolic androgenic steroids (AAS) have medical utility but are often abused, and the effects of AAS on reward circuits in the brain have been suggested to lead to addiction. We investigated the previously reported correlations between AAS and the endogenous μ-opioid system in the rewarding properties of AAS in mice. We found that a single injection of a supraphysiological dose of natural or synthetic AAS strengthened excitatory synaptic transmission in putative ventral tegmental area (VTA) dopa...
Source
#1Elisabet Stener-Victorin (KI: Karolinska Institutet)H-Index: 65
#2Vasantha Padmanabhan (UM: University of Michigan)H-Index: 70
Last. David H. Abbott (UW: University of Wisconsin-Madison)H-Index: 2
view all 8 authors...
More than one out of ten women worldwide are diagnosed with the leading cause of female reproductive and metabolic dysfunction, polycystic ovary syndrome (PCOS). Despite its high prevalence, PCOS and its accompanying morbidities are likely under-diagnosed, averaging >2 years and 3 physicians before women are diagnosed. Although it has been intensively researched, the underlying cause(s) of PCOS have yet to be defined. In order to understand PCOS pathophysiology, its developmental origins, and ho...
44 CitationsSource
#1Marta Skórka-Majewicz (Pomeranian Medical University)H-Index: 6
#2Marta Goschorska (Pomeranian Medical University)H-Index: 9
Last. Izabela Gutowska (Pomeranian Medical University)H-Index: 20
view all 7 authors...
Abstract The effects of fluoride on endocrine tissues has not been sufficiently explored to date. The current body of knowledge suggest significant effects of that mineral on reducing sex hormone levels, which may consequently impair fertility and disrupt puberty. The majority of studies confirm that sodium fluoride increases TSH levels and decreases the concentrations of T3 and T4 produced by the thyroid. Moreover, a correlation was observed between NaF and increased secretion of PTH by the par...
5 CitationsSource
#1Stephen Franks (Imperial College London)H-Index: 83
#2Kate Hardy (Imperial College London)H-Index: 45
Abstract Anovulation in PCOS is characterised by arrest of antral follicles, a phenotype that can be rescued by increasing circulating concentrations of FSH. Abnormalities of gonadotropin regulation, secretion and action have been implicated in the aetiology of anovulation, as well as local, intraovarian factors. Recent studies have implicated both central and intraovarian actions of AMH in the aetiology of PCOS and in the mechanism of anovulation. It is likely that more than one pathway is invo...
3 CitationsSource
#1V.R.P. Barros (UNIVASF: Universidade Federal do Vale do São Francisco)H-Index: 6
#2A.P.O. Monte (UNIVASF: Universidade Federal do Vale do São Francisco)H-Index: 5
Last. M. H. T. Matos (UNIVASF: Universidade Federal do Vale do São Francisco)H-Index: 10
view all 11 authors...
Abstract The aim of this study was to evaluate follicular survival and development of ovine isolated secondary follicles cultured in medium containing fixed or sequential concentrations of melatonin and further oocyte maturation. Isolated secondary follicles were cultured for 18 days in α-MEM+ alone (control) or with different concentrations of melatonin (100, 500 or 1000 pg/mL) or sequential concentrations of melatonin (Mel Seq: Day 6= 100; Day 12= 500; Day 18=1000 pg/mL). The percentages of mo...
4 CitationsSource