January 2024
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2 Reads
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January 2024
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2 Reads
December 2023
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24 Reads
Endocrinology
Hyperandrogenism and polycystic ovarian syndrome (PCOS) result from the imbalance or increase of androgen levels in females. Androgen Receptor (AR) mediates the effects of androgens, and this study examines whether neuronal AR plays a role in reproduction under normal and increased androgen conditions in female mice. The neuron specific AR knockout mouse (SynARKO) was generated from a female mouse (synapsin promoter driven Cre) and a male mouse (Ar fl/y). Puberty onset and the levels of reproductive hormones such as LH, FSH, testosterone and estradiol were comparable between the control and the SynARKO mice. There were no differences in cyclicity and fertility between the control and SynARKO mice, with similar impairment in both groups upon dihydrotestosterone (DHT) treatment. Neuronal AR KO, as in this SynARKO mouse model, did not alleviate the infertility associated with DHT treatment. These studies suggest that neuronal AR KO neither altered reproductive function under physiological androgen levels, nor restored fertility under hyperandrogenic conditions.
September 2023
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22 Reads
Endocrinology
Hyperandrogenemia and polycystic ovary syndrome are a result of the imbalance of androgen levels in females. Androgen receptor (Ar) mediates the effect of androgen, and this study examines how neuronal Ar in the central nervous system mediates metabolism under normal and increased androgen conditions in female mice. The neuron-specific ARKO mouse (SynARKO) was created from female (Ar fl/wt; synapsin promoter driven Cre) and male (Ar fl/y) mice. A glucose tolerance test revealed impaired glucose tolerance that was partially alleviated in the SynARKO-dihydrotestosterone (DHT) mice compared with Con-DHT mice after 4 months of DHT treatment. Heat production and food intake was higher in Con-DHT mice than in Con-veh mice; these effects were not altered between SynARKO-veh and SynARKO-DHT mice, indicating that excess androgens may partially alter calorie intake and energy expenditure in females via the neuronal Ar. The pAkt/Akt activity was higher in the hypothalamus in Con-DHT mice than in Con-veh mice, and this effect was attenuated in SynARKO-DHT mice. Western blot studies show that markers of inflammation and microglia activation, such as NF-kB p-65 and IBA1, increased in the hypothalamus of Con-DHT mice compared with Con-veh. These studies suggest that neuronal Ar mediates the metabolic impacts of androgen excess in females.
April 2023
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15 Reads
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1 Citation
Current Opinion in Pediatrics
Purpose of review: The diagnostic criteria for polycystic ovary syndrome (PCOS) in adults may overdiagnose PCOS in adolescents. Since 2015, three guidelines have developed adolescent-specific diagnostic criteria and treatment recommendations. In this review, we compare and contrast the recommendations to assist in the practical application to clinical practice. Recent findings: The guidelines agree that hyperandrogenism with menstrual irregularity be diagnostic criteria for PCOS in adolescents yet have slight differences in how to diagnose hyperandrogenism and in the definition of menstrual irregularity. The diagnostic option of 'at risk for PCOS' is recommended for those girls presenting with criteria within 3 years of menarche or with hyperandrogenism without menstrual irregularity, with re-assessment later in adolescence. Lifestyle changes is first line treatment. Treatment with combined oral contraceptives or metformin is suggested, using patient characteristics and preferences to guide decision-making. Summary: PCOS is associated with long term reproductive and metabolic complications and will present during adolescence. Yet, diagnostic features may overlap with normal adolescent physiology. The recent guidelines strove to develop criteria to accurately identify girls with PCOS allowing early surveillance and treatment yet avoid overdiagnosis of normal adolescents.
March 2023
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133 Reads
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3 Citations
Nonbinary individuals, or those who identify outside of the traditional gender binary, are currently present in up to 9% of the general population of youth or up to 55% of gender-diverse youth. Despite the high numbers of nonbinary individuals, this population continues to experience barriers to healthcare due to providers’ inability to see beyond the transgender binary and lack of competence in providing nonbinary care. In this narrative review, we discuss using embodiment goals to individualize care of nonbinary individuals, and review hormonal and nonhormonal treatment options for gender affirmation. Hormonal treatments include those often used in binary transgender individuals, such as testosterone, estradiol, and anti-androgens, but with adjustments to dosing or timeline to best meet a nonbinary individual’s embodiment goals. Less commonly used medications such as selective estrogen receptor antagonists are also discussed. For nonhormonal options, alterations in gender expression such as chest binding, tucking and packing genitalia, and voice training may be beneficial, as well as gender-affirming surgeries. Many of these treatments lack research specific to nonbinary individuals and especially nonbinary youth, and future research is needed to ensure safety and efficacy of gender-affirming care in this population.
November 2022
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13 Reads
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2 Citations
Journal of Adolescent Health
Purpose To compare the efficacy of intramuscular Lupron and subcutaneous Eligard, two formulations of leuprolide, for puberty suppression in transgender and gender diverse (TGD) youth. Methods A retrospective chart review of TGD youth receiving Lupron or Eligard 22.5 mg every 3 months was conducted to determine hormone levels obtained 1 hour after an injection (1hrPost) and patient-reported clinical puberty suppression. Results Forty eight patients were analyzed: 33% assigned female at birth of which 25% were premenarchal, mean age at first injection 13.7 years, and 50% received concurrent gender affirming hormones. Of these, 13% received Lupron, 52% Eligard, and 35% initially received Lupron then transitioned to Eligard due to drug shortages. There were 55 incidents of 1hrPost levels, 42 after Eligard and 13 after Lupron. Clinical puberty suppression occurred in all patients; however, biochemical suppression occurred in 90% of Eligard and 69% of Lupron (p = .06). Discussion Eligard and Lupron were both effective in suppressing clinical puberty progression in our population of TGD youth, of which 50% were receiving concurrent gender affirming hormones.
September 2022
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16 Reads
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3 Citations
Transgender Health
June 2022
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55 Reads
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3 Citations
Obesity, altered glucose homeostasis, hyperinsulinism, and reproductive dysfunction develops in female humans and mammals with hyperandrogenism. We previously reported that low dose dihydrotestosterone (DHT) administration results in metabolic and reproductive dysfunction in the absence of obesity in female mice, and conditional knock-out of the androgen receptor (Ar) in the liver (LivARKO) protects female mice from DHT-induced glucose intolerance and hyperinsulinemia. Since altered metabolic function will regulate reproduction, and liver plays a pivotal role in the reversible regulation of reproductive function, we sought to determine the reproductive phenotype of LivARKO mice under normal and hyperandrogenemic conditions. Using Cre/Lox technology, we deleted the Ar in the liver, and we observed LivARKO female mice have normal puberty timing, cyclicity and reproductive function. After DHT treatment, like control mice, LivARKO experience altered estrous cycling, reduced numbers of corpus lutea, and infertility. Liver Ar is not involved in hyperandrogenemia-induced reproductive dysfunction. The reproductive dysfunction in the DHT-treated LivARKO lean females with normal glucose homeostasis indicates that androgen-induced reproductive dysfunction is independent from metabolic dysfunction.
April 2022
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71 Reads
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1 Citation
The kisspeptin receptor, crucial for hypothalamic control of puberty and reproduction, is also present in the pituitary gland. Its role in the pituitary gland is not defined. Kisspeptin signaling via the Kiss1r could potentially regulate reproductive function at the level of pituitary gonadotrope. Using Cre/Lox technology, we deleted the Kiss1r gene in pituitary gonadotropes (PKiRKO). PKiRKO males have normal genital development (anogenital distance WT: 19.1 ± 0.4 vs. PKiRKO: 18.5 ± 0.4 mm), puberty onset, testes cell structure on gross histology, normal testes size, and fertility. PKiRKO males showed significantly decreased serum FSH levels compared to WT males (5.6 ± 1.9 vs. 10.2 ± 1.8 ng/ml) with comparable LH (1.1 ± 0.2 vs. 1.8 ± 0.4 ng/ml) and testosterone levels (351.8 ± 213.0 vs. 342.2 ± 183.0 ng/dl). PKiRKO females have normal puberty onset, cyclicity, LH and FSH levels and fertility. Overall, these findings indicate that absence of pituitary Kiss1r reduces FSH levels in male mice without affecting testis function. PKiRKO mice have normal reproductive function in both males and females.
January 2022
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14 Reads
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1 Citation
Academic Pediatrics
Objective : A structured oral exam (SOE) can be utilized as a formative assessment to provide high-quality formative feedback to trainees, but has not been adequately studied in graduate medical education. We obtained fellow and faculty perspectives on: 1) educational effectiveness; 2) feasibility/acceptability; and 3) time/cost of a SOE for formative feedback. Methods : Four pediatric endocrinology cases were developed and peer-reviewed to generate a SOE. The exam was administered by faculty to pediatric endocrinology fellows individually, with feedback after each case. Fellow/faculty perspectives of the SOE were obtained through a questionnaire. Qualitative thematic analysis was utilized to analyze written comments generated by faculty and fellows. Results : Seven of 10 pediatric endocrinology fellowship programs and all 18 fellows within those programs agreed to participate. Thematic analysis of fellow and faculty comments resulted in five perceived advantages of the SOE: 1) improved identification of clinically relevant knowledge deficits; 2) improved assessment of clinical reasoning; 3) immediate feedback/teaching; 4) assurance of adequate teaching/assessment of uncommon cases; and 5) more clinically relevant assessment. Mean time to administer one case was 15.8 minutes (2.0) and was mentioned as a potential barrier to implementation. Almost all fellows (17/18, 94%) and faculty (6/7, 86%) would recommend or would most likely recommend implementation of the SOE into their curriculum. Conclusions : The SOE utilized for formative feedback was perceived by fellows and faculty to have several educational advantages over current assessments and high acceptability. Objective educational advantages should be assessed on future studies of the SOE.
... The low-glycemic-index diet has also [44] shown a positive impact on inflammatory marker decreases and IR improvement, as also confirmed by others [45,46]. It is important to focus not so much on the total intake of carbohydrates, but more on the type of carbohydrates that are consumed, since a diet rich in unrefined foods and soluble fiber has been associated with greater insulin sensitivity [4]. ...
April 2023
Current Opinion in Pediatrics
... Marwa et al. (2022) examined bone mineral density data from 119 transgender youths; they found that boys who wished to be girls start off with low bone mineral density even prior to treatment, which is attributed to low body mass index and vitamin D insufficiency. Other studies have found similar results (e.g., Hodax & DiVall, 2023;Schagen et al., 2020). Lee et al. (2020) suggested that the cause of low bone mineral density may be low activity levels in these youths. ...
Reference:
No Bones About It: Sex Is Binary
March 2023
... With either discontinuation of puberty blockers or addition of GAH, growth velocity will increase to pubertal norms [36][37][38]. Some studies have shown that prepubertal TGD youth have bone mineral density (BMD) Z-scores that are below average but within normal ranges for reference standards for sex assigned at birth [39][40][41]. Bone mass accrual is dependent on sex steroid hormones [39]. Therefore, there is an expected decrease in BMD Z-scores during treatment with puberty blockers, which improves after the addition of GAH [39,42,43]. ...
September 2022
Transgender Health
... Muscle-specific AR knockout models displayed similar traits to controls after DHT exposure; however, some aberrant metabolic phenotypes ameliorated in adipose tissue-specific AR knockout mice, but not the reproductive features (113). The deletion of AR in the liver results in restored metabolic functions, such as impaired glucose homeostasis, whereas similar reproductive deficits remained in the control group after DHT exposure (114). Overall, these findings depict the key AR target sites outside of the ovary, including the brain, liver, and adipose tissues, and the crucial roles they play in the development of PCOS. ...
June 2022
... It was shown that KPs can activate KPRs in a pituitary gonadotroph cell line LbT2 and induce protein kinase C-dependent expression of FSHb and LHb (80). In contrast, a recent study has demonstrated that pituitary-specific knockout of KPRs reduced the FSH level in male mice, but not the LH level or testicular function (81). Neither GPN levels in female mice nor the reproductive function in male or female mice was affected following the loss of KPRs in pituitary gland (81). ...
April 2022
... Primary mouse hepatocytes, HSCs, and LSECs were isolated as described, [24][25][26] but we used portal vein and noncirculating perfusion. The HSCs were seeded in 24well plates at a density of 130,000 cells/cm 2 on the day of isolation (day 0). ...
October 2021
Journal of Visualized Experiments
... The close relationship between androgen and IR has long been reported. Accumulating studies show that androgen can affect insulin signaling and insulin sensitivity in adipose tissue [10], skeletal muscle [11], liver [12], and uterus [13], suggesting that excessive androgen contributes to IR in PCOS. Hyperinsulinemia has been considered as a compensatory consequence of IR [14]. ...
September 2021
... The DNA-binding domain is highly conserved and contains two zinc fingers that guide the binding of AR to the androgen response elements (AREs) to activate or repress transcription of AR-regulated genes (16). In addition to this DNA-binding-dependent action, cytosolic AR also activates second messenger signaling pathways such as extracellular signal-regulated kinase (ERK) and mitogen-activated protein kinase (MAPK) (17). Given that cytosolic AR can signal in this manner, there has been increased interest in the mechanisms by which androgens control cellular organelle function. ...
June 2021
... The treatment regimen normally consists of an ongoing daily injection throughout childhood and adolescence until obtaining adult height [22]. With early diagnosis and treatment initiation, children with GHD often achieve a height within the normal range for their family; research further indicates beneficial impacts on their social and emotional well-being [5,7,[23][24][25]. In the US, a retrospective review of two claims databases for children diagnosed with GHD between 2007 and 2018 who were insured by either Medicaid (n = 6820) or commercial health insurance (n = 14,070) found 63.2% (Medicaid) and 68.4% (commercial) GHD patients were treated at some point with somatropin [26]. ...
November 2019
Current Opinion in Endocrinology, Diabetes, and Obesity
... According to this guideline, diagnosis of PCOS requires a minimum of two out of the three following features: (1) androgen excess confirmed by a blood test, (2) ovulatory dysfunction, or/and (3) 12 or more cysts on an ovary/or an ovarian volume of more than 10 mL [3]. However, adolescent diagnosis of PCOS is different in that some criteria tend to imbricate with the normal physiology of a developing female reproductive system [4]. PCOS is generally characterized by hormonal imbalances that occur when the ovaries produce excess androgens [1]. ...
August 2019
Pediatric Annals