Precocious Puberty: Causes, Consequences, Daily Environmental Factors, and the need for Community/Societal Support

Precocious puberty, otherwise described as a group of medical conditions that cause early puberty onset, such as a pre-adolescent boy presenting with adult pattern of penile and testicular enlargement or a pre-adolescent girl presenting with mature breast development and onset of menses. Although the sexual and physical characteristics for this condition are well-described in medical literature, the causes are very rarely known. Nevertheless, it has substantial impacts on children’s lives. This is a review on sexual development, premature sexual development, the social complications children suffer from due to early onset puberty, and the associations with daily environmental exposures as possible influences for developing precocious puberty.

Early-life exposures and age at thelarche in the Sister Study cohort

Background Early age at breast development (thelarche) has been associated with increased breast cancer risk. Average age at thelarche has declined over time, but there are few established risk factors for early thelarche. We examined associations between pre- and postnatal exposures and age at thelarche in a US cohort of women born between 1928 and 1974. Methods Breast cancer-free women ages 35–74 years who had a sister diagnosed with breast cancer were enrolled in the Sister Study from 2003 to 2009 (N = 50,884). At enrollment, participants reported information on early-life exposures and age at thelarche, which we categorized as early (≤ 10 years), average (11–13 years), and late (≥ 14 years). For each exposure, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for early and late thelarche using polytomous logistic regression, adjusted for birth cohort, race/ethnicity and family income level in childhood. Results Early thelarche was associated with multiple prenatal exposures: gestational hypertensive disorder (OR = 1.25, 95% CI 1.09–1.43), diethylstilbestrol use (OR = 1.23, 95% CI 1.04–1.45), smoking during pregnancy (OR = 1.20, 95% CI 1.13–1.27), young maternal age (OR 1.30, 95% CI 1.16–1.47 for < 20 vs. 25–29 years), and being firstborn (OR = 1.25, 95% CI 1.17–1.33). Birthweight < 2500 g and soy formula use in infancy were positively associated with both early and late thelarche. Conclusions Associations between pre- and postnatal exposures and age at thelarche suggest that the early-life environment influences breast development and therefore may also affect breast cancer risk by altering the timing of pubertal breast development.

Rare case of two siblings with complete androgen insensitivity syndrome

Androgen insensitivity syndrome (AIS) also called testicular feminizing syndrome is a rare X linked disorder of sexual differentiation caused by mutation in the androgen receptor (AR) gene, which is located on the X chromosome (Xq11-q12). In the reported cases, individuals with complete androgen insensitivity syndrome (CAIS) presented with a female appearance and normal breast development, absence of uterus and ovaries, bilateral undescended testis, and elevated testosterone levels. The syndrome is usually detected on evaluation of a phenotypic female with primary amenorrhea who presents for treatment of infertility. Here, we report 2 cases of CAIS in siblings 21 and 19 years of age who presented to us with primary amenorrhea. The elder sibling presented to us with primary amenorrhea, thelarche +, absent adrenarche, blind pouch of vagina, b/l inguinal masses suggestive of undescended testes, raised serum testosterone and absent uterus on USG. While the younger sibling also presented with similar findings but had history of b/l orchidectomy at the age of 14 years. Both the sisters were admitted in our unit and the elder sister underwent b/l orchidectomy and McIndoe’s vaginoplasty. While the younger sister underwent McIndoe’s vaginoplasty on the same day. Post-operative recovery was uneventful and they were given hormone replacement therapy (HRT). AIS is a rare X linked disease caused by mutation in the AR gene. which when diagnosed early can be treated appropriately. Precise diagnosis requires clinical, hormonal and molecular investigation and is of great importance for appropriate gender assignment and management in general. With timely gonadectomy, vaginoplasty or vaginal pouch deepening, hormone replacement and appropriate psychological support help the person live a healthy and almost normal life.

An Approach to the Evaluation and Management of the Obese Child with Early Puberty

With the decline in age at onset of puberty and increasing prevalence of childhood obesity, early breast development in young, obese girls has become a more frequent occurrence. Here, we examine available literature to answer a series of questions regarding how obesity impacts the evaluation and management of precocious puberty. We focus on girls as the literature is more robust, but include boys where literature permits.Suggestions include: (1) Age cut-offs for evaluation of precocious puberty should not differ substantially from those used for non-obese children. Obese girls with confirmed thelarche should be evaluated for gonadotropin-dependent, central precocious puberty (CPP) to determine if further investigation or treatment is warranted. (2) Basal luteinizing hormone (LH) levels remain a recommended first-line test. However, if stimulation testing is utilized, there is a theoretical possibility that the lower peak LH responses seen in obesity could lead to a false negative result. (3) Advanced bone age (BA) is common among obese girls even without early puberty; hence its diagnostic utility is limited. (4) Obesity does not eliminate the need for MRI in girls with true CPP. Age and clinical features should determine who warrants neuroimaging. (5) BA can be used to predict adult height in obese girls with CPP to inform counselling around treatment. (6) Use of gonadotropin-releasing hormone analogues (GnRHa) leads to increased adult height in obese girls. (7) Obesity should not limit GnRHa use as these agents do not worsen weight status in obese girls with CPP.

Understanding Breast Health Awareness Among Nurses during conflict in Yemen

PURPOSE: The aim of this study was to determine the knowledge of risk factors and symptoms of breast cancer among Yemeni nurses during the conflict. METHODOLOGY: A cross-sectional design was carried out among 392 randomly selected participants. The instrument consists of 20 items, 12 general awareness statements, and 8 curability statements with a 0.711 reliability coefficient. Data analysis was performed using SPSS version 25. RESULTS: Most of the nurses were female (69.5%), with a mean age of 28.54, with monthly income less than 200 USD (54.3%). About 21.4% of the participants were smokers. Among all participants, the most frequently mentioned risk factor were breastfeeding, reducing the risk of breast development (86.2%), followed by physical activities lowers the developing risk of breast cancer (79.1%). Over time, the myth of the constant irritation due to the tight bra may cause breast cancer reported by women more than male nursing students. In this respect, men were better knowledgeable than women (P=0.001). Females, however, were more aware than males that women who bear their first child before 30 are more to develop breast cancer (P=0.017). Income is significantly associated with the level of knowledge among nurses. The most frequently mentioned breast symptoms among all participants were a pain in the breast (82.9%), followed by changes in the breast shape (79.1%). CONCLUSIONS: Income is significantly associated with the level of knowledge among nurses. The myth about breast cancer is dominant among nurses in Yemen. Therefore, there is an urgent need to educate nurses on breast health.

A CASE REPORT ON ANDROGEN INSENSITIVITY SYNDROME

Androgen Insensitivity Syndrome is an X linked disorder resulting in normal masculinization of external genitalia due to loss of function mutation in AR gene. Case Report : A 18 year old female presented with C/O not attaining menarche. Patient gives a history of lack of development of pubic and axillary hair. No history of abnormal breast development,cyclical abdominal pain or excessive weight gain. No relevant family history. O/E No palpable swellings in abdomen or bilateral inguinal region. External genitalia appear like a normal female external genitalia. The patient's karyotyping was done and it is of male genotype. The patient is diagnosed as Complete AIS as the phenotype is female and genetically male. The patient is managed by laparoscopic B/L orchidectomy with B/L deep ring closure.

Biological Mechanisms and Therapeutic Opportunities in Mammographic Density and Breast Cancer Risk

Mammographic density is an important risk factor for breast cancer; women with extremely dense breasts have a four to six fold increased risk of breast cancer compared to women with mostly fatty breasts, when matched with age and body mass index. High mammographic density is characterised by high proportions of stroma, containing fibroblasts, collagen and immune cells that suggest a pro-tumour inflammatory microenvironment. However, the biological mechanisms that drive increased mammographic density and the associated increased risk of breast cancer are not yet understood. Inflammatory factors such as monocyte chemotactic protein 1, peroxidase enzymes, transforming growth factor beta, and tumour necrosis factor alpha have been implicated in breast development as well as breast cancer risk, and also influence functions of stromal fibroblasts. Here, the current knowledge and understanding of the underlying biological mechanisms that lead to high mammographic density and the associated increased risk of breast cancer are reviewed, with particular consideration to potential immune factors that may contribute to this process.

The role of estrone in feminizing hormone treatment

Context In trans women, hormone treatment induces feminization, however the degree of feminization varies from person to person. A possible contributing factor could be estrone, a weak estrogen that interferes with the estrogen receptor. Objective To assess whether estrone is involved in feminization induced by hormone treatment. Design Prospective cohort study, with one year follow-up. Setting Gender identity clinic. Participants 212 adult trans women, starting hormone treatment between July 2017 and December 2019, median age 25 years. Intervention Gender affirming hormone treatment. Main outcome measures Change in fat percentage and breast development. Results After 12 months of hormone treatment, estrone concentration was 187pmol/L (95%CI 153 – 220) in transdermal and 1516pmol/L (95%CI 1284 – 1748) in oral estradiol users. Fat percentage increased by 1.2% (IQR 0.3 – 4.8) in transdermal and 4.6% (IQR 2.5 – 5.9) in oral estradiol users. This was not associated with estrone concentrations in transdermal(+4.4% (95%CI -4.0 – 13) per 100pmol/L increase in estrone concentration) nor in oral estradiol users (-0.7% (95%CI -1.7 – 0.3)). Breast volume increased by 69ml (IQR 58 – 134) in transdermal and 62ml (IQR 32 – 95) in oral estradiol users. This was not associated with estrone concentrations in transdermal (+ 14% (95%CI -49 – 156) per 100pmol/L increase in estrone concentration) nor oral estradiol users (+ 11% (95%CI -14 – 43)). Conclusions Change in fat percentage and breast development in trans women were not associated with estrone concentrations nor with administration route. Therefore measurement of estrone concentrations does not have a place in the monitoring of feminization in trans women.

Disorders of Puberty in Girls

Puberty is the process through which reproductive competence is achieved and comprises gonadarche and adrenarche. Breast development is the initial physical finding of pubertal onset in girls and typically occurs between 8 and 13 years. Menarche normally occurs 2 to 3 years after the onset of breast development. Pubertal onset is controlled by the gonadotropin-releasing hormone pulse generator in the hypothalamus; however, environmental factors such as alterations in energy balance and exposure to endocrine-disrupting chemicals can alter the timing of pubertal onset. Improvement in nutritional and socioeconomic conditions over the past two centuries has been associated with a secular trend in earlier pubertal onset. Precocious puberty is defined as onset of breast development prior to 8 years and can be central or peripheral. Delayed puberty can be hypogonadotropic or hypergonadotropic and is defined as lack of breast development by 13 years or lack of menarche by 16 years. Both precocious and delayed puberty may have negative effects on self-esteem, potentially leading to psychosocial stress. Patients who present with pubertal differences require a comprehensive assessment to determine the underlying etiology and to devise an effective treatment plan.

Central Precocious Puberty in a Three-Year-Old Girl

Precocious puberty is defined as the onset of secondary sexual characteristics before 8 years of age in girls and 9 years in boys. Central Precocious Puberty (CPP) is caused by early activation of the hypothalamic-pituitary-gonadal axis. Laboratory test of LH, FSH, and Estradiol is recommended for monitoring suppressive effects from GnRHa therapy in the early three months and every six months. This study aimed to report a case of CPP in a 3-year and 3-month-old girl. A 3-year and 3-month-old girl went to the hospital with vaginal bleeding (menstruation), breast development, and pubic and axilla hair for 7-month-old. Physical examination found moderately ill with obesity, body weight 20 kg, height 98 cm. Tanner stage was A2M3P2, café au lait was found in the left forehead with size 7x3.5 cm. In March 2015 before GnRHa therapy, LH, FSH and Estradiol level increased with levels of 4.32 mlU/mL, 6.01 mlU/mL, and 67 pg/mL, and after 3 months of the treatment was 0.87 mlU/mL, 2.51 mlU/mL and <20 pg/mL. Pelvic ultrasonography showed suggestive precocious puberty, bone age 5-year and 9-month (Greulich and Pyle), CT-Scan of the brain showed hypothalamic tumor suspected hypothalamic hamartoma. This patient was treated with a GnRHa injection every 4 weeks. Leuprorelin is a synthetic non-peptide analogue of natural GnRH. The diagnosis was based on medical history, physical examination, laboratory, and radiological findings. The prognosis of the patient was good.