scholarly journals Mice With Targeted Deletion of ARC Kisspeptin Exhibit Immature Gametogenesis and Impaired Fertility

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A543-A544
Author(s):  
Nimisha Nandankar ◽  
Ariel L Negron ◽  
Andrew M Wolfe ◽  
Jon E Levine ◽  
Sally Radovick
Keyword(s):  
Antral Follicle ◽  
Mature Sperm ◽  
Seminiferous Tubules ◽  
Corpora Lutea ◽  
Knock Out ◽  
Targeted Deletion ◽  
Female Mice ◽  
Lh Pulsatility ◽  
Estrous Cyclicity ◽  
Fertility Data

Abstract Hypothalamic kisspeptin is primarily synthesized in two discrete nuclei - the anteroventral periventricular (AVPV) and the arcuate (ARC) nuclei. We have previously developed a selective, conditional ARC kisspeptin knock-out (KO) mouse line, namely the Pdyn-Cre/Kissfl/fl KO mice, that exhibited normal puberty onset in both sexes, but impaired estrous cyclicity and LH pulsatility in Pdyn-Cre/Kissfl/fl KO females. To examine the end-organ effect of the lack of ARC kisspeptin, we examined gametogenesis, gonad morphology, and fertility. Hematoxylin and eosin (H&E) staining of serial-sectioned whole ovaries demonstrated that Pdyn-Cre/Kissfl/fl KO female mice lacked corpora lutea - their ovarian folliculogenesis did not progress beyond antral follicle development, suggesting an ovulatory defect in Pdyn-Cre/Kissfl/fl KO females. 75% of the Pdyn-Cre/Kissfl/fl KO male mice had testes exhibiting a striking decrease in mature sperm in the seminiferous tubules. The remaining 25% showed evidence of mature sperm. Further evidence of a hypogonadal phenotype of the Pdyn-Cre/Kissfl/fl KO mice included the significantly low weight and small size of the ovaries, uteri, and testes when compared to control littermates. In a controlled, continuous mating paradigm with proven WT males, 2-4-month-old Pdyn-Cre/Kissfl/fl KO female mice failed to become pregnant or produce any pups, whereas age-matched WT females exhibited normal pregnancies to term. Thus, Pdyn-Cre/Kissfl/fl KO females have complete infertility. Ongoing studies of male fertility data suggest that Pdyn-Cre/Kissfl/fl KO males are subfertile, in accordance with their variable spermatogenesis phenotype - some KO males sired pups when paired with proven, WT females, whereas other KO males are infertile. Future experiments include assessing the capability of Pdyn-Cre/Kissfl/fl KO mice to respond to chronic, exogenous kisspeptin and GnRH administration to rescue abnormal LH pulsatility and estrous cyclicity in females, as well as the impaired fertility in both sexes.

scholarly journals Deficiency of Arcuate Nucleus Kisspeptin Results in Post-Pubertal Central Hypogonadism

2021 ◽  
Author(s):  
Nimisha Nandankar ◽  
Ariel L. Negron ◽  
Andrew Wolfe ◽  
Jon E Levine ◽  
Sally Radovick
Keyword(s):  
Feedback Control ◽  
Arcuate Nucleus ◽  
Critical Role ◽  
Knock Out ◽  
Protein Levels ◽  
Reproductive Axis ◽  
Lh Pulsatility ◽  
Estrous Cyclicity ◽  
Lh Release ◽  
Kndy Neurons

Kisspeptin (encoded by Kiss1), a neuropeptide critically involved in neuroendocrine regulation of reproduction, is primarily synthesized in two hypothalamic nuclei: the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC). AVPV kisspeptin is thought to regulate the estrogen-induced positive feedback control of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH), and the pre-ovulatory LH surge in females. In contrast, ARC kisspeptin neurons, which largely co-express neurokinin B and dynorphin A (collectively named KNDy neurons), are thought to mediate estrogen-induced negative feedback control of GnRH/LH and be the major regulators of pulsatile GnRH/LH release. However, definitive data to delineate the specific roles of AVPV versus ARC kisspeptin neurons in the control of GnRH/LH release is lacking. Therefore, we generated a novel mouse model targeting deletion of Kiss1 to the ARC nucleus (Pdyn-Cre/Kiss1fl/fl KO) to determine the functional differences between ARC and AVPV kisspeptin neurons on the reproductive axis. The efficacy of the knock-out was confirmed at both the mRNA and protein levels. Adult female Pdyn-Cre/Kiss1fl/fl KO mice exhibited persistent diestrus and significantly fewer LH pulses when compared to controls, resulting in arrested folliculogenesis, hypogonadism, and infertility. Pdyn-Cre/Kiss1fl/fl KO males also exhibited disrupted LH pulsatility, hypogonadism, and variable, defective spermatogenesis and subfertility. The timing of pubertal onset in males and females was equivalent to controls. These findings add to the current body of evidence for the critical role of kisspeptin in ARC KNDy neurons in GnRH/LH pulsatility in both sexes, while directly establishing ARC kisspeptin's role in regulating estrous cyclicity in female mice, and gametogenesis in both sexes, and culminating in disrupted fertility. The Pdyn-Cre/Kiss1fl/fl KO mice present a novel mammalian model of post-pubertal central hypogonadism.

scholarly journals Free Fatty Acids Induce Lhb mRNA but Suppress Fshb mRNA in Pituitary LβT2 Gonadotropes and Diet-Induced Obesity Reduces FSH Levels in Male Mice and Disrupts the Proestrous LH/FSH Surge in Female Mice

Endocrinology ◽  
2013 ◽  
Vol 154 (6) ◽  
pp. 2188-2199 ◽  
Author(s):  
Shweta Sharma ◽  
Hidetaka Morinaga ◽  
Vicky Hwang ◽  
WuQiang Fan ◽  
Marina O. Fernandez ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Free Fatty Acids ◽  
Mrna Expression ◽  
High Fat Diet ◽  
Mapk Signaling ◽  
Seminiferous Tubules ◽  
Corpora Lutea ◽  
Toll Like Receptor ◽  
High Fat ◽  
Female Mice

Abstract Female obesity is associated with insulin resistance, hyperandrogenemia, and reproductive dysfunction. We hypothesized that elevated free fatty acids (FFAs) might directly modulate pituitary gonadotropin production. FFAs caused a time- and dose-dependent increase in phosphorylation of the MAPKs p38MAPK, c-Jun N-terminal kinase (JNK)-1/2, and ERK1/2 in LβT2 gonadotrope cells. Furthermore, FFAs up-regulated Lhb mRNA expression acutely, an effect that was blocked by JNK inhibition, but suppressed Fshb mRNA expression, an effect that was independent of MAPK signaling. FFAs enhanced the activation of the MAPKs in the presence of GnRH, although the cotreatment did not alter Lhb induction but did eliminate the GnRH induction of Fshb. FFAs also suppressed activin-induced Fshb expression. Knockdown experiments showed that the FFA effect on the inflammatory kinases p38MAPK and JNK and on Lhb, but not Fshb, mRNA expression is mediated via toll-like receptor-2 and toll-like receptor-4 and was mimicked by lipopolysaccharide stimulation. In vivo, male C57BL/6 mice on a high-fat diet showed reduced FSH levels consistent with the suppression of Fshb seen in vitro. Histological analysis of the testes showed an increased number of abnormal seminiferous tubules. Female mice on a high-fat diet lacked the expected proestrus LH and FSH surge and exhibited an increase in the number of days at estrus and a reduced number of days at proestrus, and ovaries had significantly fewer corpora lutea. Taken together, our findings suggest that lipid excess can lead to reproductive defects in both male and female mice.

scholarly journals SUN-243 Deletion of KNDy Neuron-Specific KISS1 Disrupts Estrous Cyclicity and LH Pulsatility in Female Mice

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Nimisha Nandankar ◽  
Ariel L Negron ◽  
Jon E Levine ◽  
Sally Radovick
Keyword(s):  
Feedback Control ◽  
Negative Feedback ◽  
Vaginal Opening ◽  
Pulsatile Release ◽  
Female Mice ◽  
Lh Pulsatility ◽  
Estrous Cyclicity ◽  
Lh Release ◽  
Negative Feedback Control ◽  
Kndy Neurons

Abstract Kisspeptin (encoded by Kiss1), a neuropeptide critically involved in neuroendocrine regulation of reproduction, is primarily synthesized in two discrete hypothalamic nuclei: the anteroventral periventricular area (AVPV) and arcuate nucleus (ARC). AVPV Kiss1 is important for the pre-ovulatory luteinizing hormone (LH) surge unique to females as well as estrogen-induced positive feedback control of GnRH and LH. In contrast, ARC Kiss1 neurons, which largely co-express the neuropeptides NKB and dynorphin (collectively known as KNDy neurons), are major regulators of pulsatile release of GnRH and LH, and mediate estrogen-induced negative feedback control of both GnRH and LH. Previous studies have not fully separated the specific roles for Kiss1 in the AVPV versus KNDy-ARC neurons in the downstream control of GnRH and LH release. Therefore, we generated a Pdyn-Cre/Kiss1fl/fl (KO) mouse model to target Kiss1 in the KNDy neurons to differentiate KNDy neuron-specific function from AVPV Kiss1 function in the maturation and maintenance of the reproductive axis. qRT-PCR data documented a significant reduction of Kiss1 expression in the mediobasal hypothalamus (containing ARC) compared to controls, whereas Kiss1 in the preoptic area (containing AVPV) was similar in both KO and controls. Immunofluorescent IHC confirmed a loss of kisspeptin immunoreactivity in the ARC of KO animals while expression in the AVPV remained intact. Markers of pubertal onset (day of vaginal opening and first estrus in females; day of preputial separation in males) were normal in KO mice, suggesting that AVPV Kiss1 and/or other neural signals may be sufficient for pubertal onset. In addition, body weight throughout pubertal growth was comparable between KO and control animals of both sexes. Interestingly, KO female mice had disrupted estrous cycles presenting with persistent diestrus and a small vaginal opening. In order to test our hypothesis that conditional deletion of Kiss1 in KNDy neurons disrupts or ablates episodic GnRH/LH pulsatile release, we collected serial tail blood samples from mice at diestrus and measured LH. KO female mice exhibited significantly fewer LH pulses in a 3-hour timespan compared to controls, suggesting that KNDy neurons were functionally compromised. These observations indicate the central role of KNDy neurons in the regulation of GnRH/LH pulsatility and estrous cyclicity. The functional effects of disrupted estrous cyclicity and slower LH pulses observed in KO females are currently under study to assess potential abnormalities in ovarian folliculogenesis and fertility. Future experiments will determine whether ARC Kiss1 deletion disrupts the KNDy-driven negative feedback response of LH to gonadectomy, as well as address potential sex differences in ARC Kiss1-mediated negative feedback control of LH release.

scholarly journals Subfertility in androgen-insensitive female mice is rescued by transgenic FSH

2017 ◽  
Vol 29 (7) ◽  
pp. 1426 ◽  
Author(s):  
K. A. Walters ◽  
M. C. Edwards ◽  
M. Jimenez ◽  
D. J. Handelsman ◽  
C. M. Allan
Keyword(s):  
Androgen Receptor ◽  
Litter Size ◽  
Ovarian Function ◽  
Reproductive Function ◽  
Antral Follicle ◽  
Female Fertility ◽  
Wild Type ◽  
Female Reproduction ◽  
Androgen Insensitivity ◽  
Female Mice

Androgens synergise with FSH in female reproduction but the nature of their interaction in ovarian function and fertility is not clear. In the present study, we investigated this interaction, notably whether higher endogenous FSH can overcome defective androgen actions in androgen receptor (AR)-knockout (ARKO) mice. We generated and investigated the reproductive function of mutant mice exhibiting AR resistance with or without expression of human transgenic FSH (Tg-FSH). On the background of inactivated AR signalling, which alone resulted in irregular oestrous cycles and reduced pups per litter, ovulation rates and antral follicle health, Tg-FSH expression restored follicle health, ovulation rates and litter size to wild-type levels. However, Tg-FSH was only able to partially rectify the abnormal oestrous cycles observed in ARKO females. Hence, elevated endogenous FSH rescued the intraovarian defects, and partially rescued the extraovarian defects due to androgen insensitivity. In addition, the observed increase in litter size in Tg-FSH females was not observed in the presence of AR signalling inactivation. In summary, the findings of the present study reveal that FSH can rescue impaired female fertility and ovarian function due to androgen insensitivity in female ARKO mice by maintaining follicle health and ovulation rates, and thereby optimal female fertility.

scholarly journals Role of ovarian sympathetic nerves and cholinergic local system during cold stress

2019 ◽  
Vol 242 (2) ◽  
pp. 115-124 ◽  
Author(s):  
Raul Riquelme ◽  
Freddy Ruz ◽  
Artur Mayerhofer ◽  
Hernán E Lara
Keyword(s):  
Cold Stress ◽  
Polycystic Ovary ◽  
Recovery Period ◽  
Sympathetic Nerves ◽  
Plasma Testosterone ◽  
Corpora Lutea ◽  
Estrous Cyclicity ◽  
Rat Ovary ◽  
The Impact ◽  
Second Period

An increase in the sympathetic tone in the rat ovary induces a polycystic ovary (PCOS-like) phenotype. No information exists about its impact on fertility. In contrast, increased follicular development and improved fertility in rats were found after pharmacological inhibition of acetylcholinesterase, which increased intraovarian acetylcholine (ACh). Now, we studied the impact of sympathetic stress, followed by a recovery period without stress, on the cholinergic and noradrenergic systems of the rat ovary and on fertility. To activate ovarian sympathetic nerves, female Sprague–Dawley rats were exposed to cold stress (4°C/3 h day for 28 days; first period), followed by a 28-day period without cold stress (second period). No changes in estrous cyclicity during the first period was found. At the end of this period, ovarian levels of NA and ACh were increased. Morphometric analysis showed lower numbers of secondary and antral follicles, enhanced follicular atresia and fewer corpora lutea. Plasma progesterone was lower and testosterone was higher than that in controls. At end of the second period, ovarian ACh levels had returned to control levels, but NA levels remained elevated. The second period was also characterized by the presence of cystic follicles in the ovary, by elevated plasma testosterone and estradiol levels, while progesterone levels were decreased. Estrous cyclicity and ovulation during that period were irregular and fertility decreased. Thus, cold stress initially activated both ovarian noradrenergic and cholinergic system. After stress, the ovary did not fully recover and activation of the noradrenergic system persisted and correlated with cystic ovarian morphology and decreased fertility.

scholarly journals Inactivation of porcine interleukin-1β results in failure of rapid conceptus elongation

2017 ◽  
Vol 115 (2) ◽  
pp. 307-312 ◽  
Author(s):  
Jeffrey J. Whyte ◽  
Ashley E. Meyer ◽  
Lee D. Spate ◽  
Joshua A. Benne ◽  
Raissa Cecil ◽  
...  
Keyword(s):  
Gene Editing ◽  
Mammalian Species ◽  
Interleukin 1Β ◽  
Corpora Lutea ◽  
Morphological Transition ◽  
Wild Type ◽  
Morphological Transformation ◽  
Proinflammatory Response ◽  
Knock Out ◽  
Estrogen Synthesis

Conceptus expansion throughout the uterus of mammalian species with a noninvasive epitheliochorial type of placentation is critical establishing an adequate uterine surface area for nutrient support during gestation. Pig conceptuses undergo a unique rapid morphological transformation to elongate into filamentous threads within 1 h, which provides the uterine surface to support development and maintain functional corpora lutea through the production of estrogen. Conceptus production of a unique interleukin 1β, IL1B2, temporally increases during the period of trophoblast remodeling during elongation. CRISPR/Cas9 gene editing was used to knock out pig conceptus IL1B2 expression and the secretion of IL1B2 during the time of conceptus elongation. Trophoblast elongation occurred on day 14 in wild-type (IL1B2+/+) conceptuses but did not occur in ILB2-null (IL1B2−/−) conceptuses. Although the morphological transition of IL1B2−/− conceptuses was inhibited, expression of a number of conceptus developmental genes was not altered. However, conceptus aromatase expression and estrogen secretion were decreased, indicating that IL1B2 may be involved in the spatiotemporal increase in conceptus estrogen synthesis needed for the establishment of pregnancy in the pig and may serve to regulate the proinflammatory response of endometrium to IL1B2 during conceptus elongation and attachment to the uterine surface.

Characterizing the neuroendocrine and ovarian defects of androgen receptor-knockout female mice

2013 ◽  
Vol 305 (6) ◽  
pp. E717-E726 ◽  
Author(s):  
Xiaobing B. Cheng ◽  
Mark Jimenez ◽  
Reena Desai ◽  
Linda J. Middleton ◽  
Shai R. Joseph ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Negative Feedback ◽  
Positive Feedback ◽  
Growth Patterns ◽  
Corpora Lutea ◽  
Preovulatory Follicle ◽  
Lh Surge ◽  
Antral Follicles ◽  
Female Mice ◽  
Follicle Diameter

Homozygous androgen receptor (AR)-knockout (ARKO) female mice are subfertile due to both intra- and extraovarian (neuroendocrine) defects as defined by ovary transplantation. Using ARKO mice, this study set out to reveal the precise AR-regulated pathways required for optimal androgen-regulated ovulation and fertility. ARKO females exhibit deficient neuroendocrine negative feedback, with a reduced serum luteinizing hormone (LH) response to ovariectomy (OVX) ( P < 0.01). Positive feedback is also altered as intact ARKO females, at late proestrus, exhibit an often mistimed endogenous ovulatory LH surge. Furthermore, at late proestrus, intact ARKO females display diminished preovulatory serum estradiol (E2; P < 0.01) and LH ( P < 0.05) surge levels and reduced Kiss1 mRNA expression in the anteroventral periventricular nucleus ( P < 0.01) compared with controls. However, this reduced ovulatory LH response in intact ARKO females can be rescued by OVX and E2 priming or treatment with endogenous GnRH. These findings reveal that AR regulates the negative feedback response to E2, E2-positive feedback is compromised in ARKO mice, and AR-regulated negative and positive steroidal feedback pathways impact on intrahypothalamic control of the kisspeptin/GnRH/LH cascade. In addition, intraovarian AR-regulated pathways controlling antral to preovulatory follicle dynamics are disrupted because adult ARKO ovaries collected at proestrus have small antral follicles with reduced oocyte/follicle diameter ratios ( P < 0.01) and increased proportions of unhealthy large antral follicles ( P < 0.05) compared with controls. As a consequence of aberrant follicular growth patterns, proestrus ARKO ovaries also exhibit fewer preovulatory follicle ( P < 0.05) and corpora lutea numbers ( P < 0.01). However, embryo development to the blastocyst stage is unchanged in ARKO females, and hence, the subfertility is a consequence of reduced ovulations and not altered embryo quality. These findings reveal that the AR has a functional role in neuroendocrine regulation and timing of the ovulatory LH surge as well as antral/preovulatory follicle development.

227 Is the antral follicle count on a random day of the oestrous cycle correlated with superovulatory responses in Santa Inês ewes?

2020 ◽  
Vol 32 (2) ◽  
pp. 241
Author(s):  
M. Pupin ◽  
G. Vergani ◽  
M. Lima ◽  
K. Silva ◽  
A. Monteiro ◽  
...  
Keyword(s):  
Pearson Correlation ◽  
Animal Health ◽  
Antral Follicle ◽  
Antral Follicle Count ◽  
Oestrous Cycle ◽  
Corpora Lutea ◽  
Embryo Recovery ◽  
Flunixin Meglumine ◽  
Santa Inês ◽  
Synchronization Protocol

Antral follicle count (AFC) performed after an oestrus synchronization protocol has been studied as a tool to select ewes with high potential for invivo embryo production (Pinto et al. 2018 Theriogenology 113, 146-152). However, it would be interesting to know whether AFC assessed on a random day of the oestrous cycle correlates with the superovulatory response. The present study was conducted to evaluate the correlation between AFC at the beginning of progesterone (P4)-based oestrus synchronization protocol used as basis of superovulatory treatment and the number of corpora lutea (CL) 12h before recovery of embryos in Santa Inês ewes. The study was conducted during September and October in northeast Brazil (03°40′26″S and 40°14′20″W) using 8 adult Santa Inês ewes. On a random day of oestrous cycle (Day 0) all ewes received an intravaginal device (CIDR) of progesterone (0.3g, Eazi-breed, Zoetis), which remained for 9 days. On Day 7, the pFSH (133mg, Folltropin V, Vetoquinol) treatment began, with 6 decreasing doses (25, 25, 15, 15, 10, and 10%) injected IM at 12-h intervals. On Day 9, 2 equal doses of D-cloprostenol were injected at a 12-h interval (37.5µg, Prolise, Agener União). All ewes showed oestrus and were mated by fertile rams. Flunixin meglumine (24.9 mg; Banamine, MSD Animal Health) was administered IM on Days 12, 13, and 15. On Day 16, non-surgical embryo recovery (NSER) was performed after cervical dilation using D-cloprostenol and oestradiol benzoate at 16h and oxytocin 20min before. Transrectal B-mode ultrasound evaluations (Z5 Vet, Mindray), frequency 7.5MHz, were performed on Day 0 and 7 and 12h before NSER to evaluate the ovarian population present. Pearson correlation analysis (P&lt;0.05) was performed using Bioestat 5.3 software. The number of AFC per ewe at the beginning of the protocol and on Day 7 were 9.9±2.7 and 11±3.2, respectively. The numbers of CL, recovered embryos, and viable embryos were 14.0±3.5, 8.2±10.9, and 6.0±11.0, respectively. There was no correlation of AFC on a random day of oestrous cycle with the number of AFC on Day 7 (P=0.42), number of corpora lutea (P=0.44), number of recovered embryos (P=0.18), or number of viable embryos (P=0.11) in superovulated ewes. In conclusion, we did not find significant correlations between AFC on a random day of oestrous cycle and the superovulatory/embryos response in Santa Inês ewes. Financial support for this study was provided by Embrapa (02.13.06.026.00.02 and 02.13.06.026.00.04) and FAPEMIG (PPM 00201-17).

scholarly journals Overaccumulation of Fat Caused Rapid Reproductive Senescence but not Loss of Ovarian Reserve in ob/ob Mice

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Mohammad Lalmoddin Mollah ◽  
Hee-Seon Yang ◽  
SoRa Jeon ◽  
KilSoo Kim ◽  
Yong-Pil Cheon
Keyword(s):  
Blood Level ◽  
Ovarian Reserve ◽  
Age Groups ◽  
Primordial Follicle ◽  
High Energy ◽  
Corpora Lutea ◽  
Mrna Levels ◽  
Physical Status ◽  
Estrous Cyclicity ◽  
17Β Estradiol

Abstract Ovarian reserve and fertility are reduced by aging and a poor energy balance. To date, the relationships of high energy accumulation and aging with the ovarian reserve have not been elucidated. Here, the effects of obesity on the aging ovarian reserve were evaluated in a leptin-deficient (ob/ob) mouse model. Abnormal estrous cyclicity appeared as early as 6 weeks and worsened with aging. The blood level patterns of 17β-estradiol (E2), testosterone (T), and progesterone (P4) with aging were similar between lean and ob/ob mice. The blood level of E2 but not P4 or T was similar at 24 weeks. Many more atretic follicles but fewer corpora lutea were observed in ob/ob mice than in lean mice within all age groups. Anti-Müllerian hormone (Amh) mRNA levels were similar between genotypes. Dazl, Stra8, and ZP3 mRNAs were highly expressed in ob/ob mice after 12 weeks. Sohlh1 and Ybx2 mRNAs were highly expressed at 24 weeks in ob/ob compared with lean mice. In addition, SOHLH1-positive primordial follicle counts were significantly increased in ob/ob mice at 24 weeks. The proportions of AMH-positive secondary and small antral follicles were similar between genotypes. Together, these results show that the ovarian reserve lasts longer in ob/ob mice than in lean mice, suggesting that the loss of normal physiological or physical status causes decreased fertility at a young age in ob/ob mice and that an increase in adipocytes without leptin, as in ob/ob mice, can improve the ovarian reserve. Such knowledge can be applied to understanding reproductive dysfunction.

scholarly journals Androgen Suppresses In Vivo and In Vitro LH Pulse Secretion and Neural Kiss1 and Tac2 Gene Expression in Female Mice

Endocrinology ◽  
2020 ◽  
Vol 161 (12) ◽  
Author(s):  
Lourdes A Esparza ◽  
Tomohiro Terasaka ◽  
Mark A Lawson ◽  
Alexander S Kauffman
Keyword(s):  
Gene Expression ◽  
Pulse Frequency ◽  
Normal Male ◽  
Steroid Abuse ◽  
Female Mice ◽  
Reproductive Axis ◽  
Lh Pulsatility ◽  
Lh Secretion

Abstract Androgens can affect the reproductive axis of both sexes. In healthy women, as in men, elevated exogenous androgens decrease gonad function and lower gonadotropin levels; such circumstances occur with anabolic steroid abuse or in transgender men (genetic XX individuals) taking androgen supplements. The neuroendocrine mechanisms by which endogenous or exogenous androgens regulate gonadotropin release, including aspects of pulsatile luteinizing hormone (LH) secretion, remain unknown. Because animal models are valuable for interrogating neural and pituitary mechanisms, we studied effects of androgens in the normal male physiological range on in vivo LH secretion parameters in female mice and in vitro LH secretion patterns from isolated female pituitaries. We also assessed androgen effects on hypothalamic and gonadotrope gene expression in female mice, which may contribute to altered LH secretion profiles. We used a nonaromatizable androgen, dihydrotestosterone (DHT), to isolate effects occurring specifically via androgen receptor (AR) signaling. Compared with control females, DHT-treated females exhibited markedly reduced in vivo LH pulsatility, with decreases in pulse frequency, amplitude, peak, and basal LH levels. Correlating with reduced LH pulsatility, DHT-treated females also exhibited suppressed arcuate nucleus Kiss1 and Tac2 expression. Separate from these neural effects, we determined in vitro that the female pituitary is directly inhibited by AR signaling, resulting in lower basal LH levels and reduced LH secretory responses to gonadotropin-releasing hormone pulses, along with lower gonadotropin gene expression. Thus, in normal adult females, male levels of androgen acting via AR can strongly inhibit the reproductive axis at both the neural and pituitary levels.

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