Isolated Premature Menarche in a 17-Month-Old: A Case Report

Introduction

Vaginal bleeding in prepubertal girls should always be investigated as it might be a manifestation of a serious medical problem [1]. Puberty is a multifaceted developmental phenomena that begins in late childhood and is characterized by the maturation of the hypothalamic-pituitary-gonadal axis. Early puberty in girls encompasses a spectrum of conditions characterized by the appearance of pubertal signs earlier than the expected age range. Precocious puberty is defined as the early onset of secondary sexual characteristics, occurring before the age of 8 years in girls and 9 years in boys, and is more commonly observed in girls. One study reported precocious puberty occurring prior to the age of 6 years in Black girls and 7 years in White girls [2,3]. The estimated incidence of precocious puberty in girls ranges from 1 in 5000 to 1 in 10 000, with central precocious puberty being the most common subtype [4]. Based on standard deviations, precocious puberty is the emergence of onset of secondary sexual characteristics earlier than 2 to 2.5 standard deviations of the mean [5,6].

Precocious puberty has been divided into central precocious puberty (gonadotropin-dependent) and peripheral precocious puberty (gonadotropin-independent) [7,8]. Central precocious puberty results from premature activation of the hypothalamic-pituitary-gonadal axis and typically presents with progressive breast development, pubic hair growth, accelerated linear growth, and advanced bone age [9]. While many cases in girls are idiopathic, central nervous system abnormalities must be excluded, particularly in children presenting at a very young age. The diagnosis is based on clinical progression, bone age advancement, basal and stimulated gonadotropin levels, and neuroimaging when indicated. Management commonly involves long-acting gonadotropin-releasing hormone analogues to suppress pubertal progression and preserve adult height potential [9].

Peripheral precocious puberty arises from estrogen production independent of hypothalamic-pituitary-gonadal axis activation and can be caused by ovarian cysts or tumors, adrenal disorders, exogenous estrogen exposure, or syndromic conditions such as McCune-Albright syndrome [4]. Laboratory evaluation typically demonstrates suppressed gonadotropin levels. Management is directed toward identification and treatment of the underlying cause [9].

In addition to true precocious puberty, several normal variants of early pubertal development should be recognized, including premature thelarche, premature adrenarche, and isolated premature menarche [4]. Isolated premature menarche is defined as vaginal bleeding in girls less than 8 years of age without any other signs of puberty; it is a diagnosis of exclusion. [10]. Other terms for this condition are premature isolated menses, isolated early menstruation, and isolated menarche [11]. The diagnosis of vaginal bleeding in prepubertal girls remains challenging; however, isolated menarche is a benign entity, with management consisting of reassurance and clinical follow-up to monitor for pubertal progression [4,10]. Isolated premature menarche presents as repeated periodic episodes of menses, usually 1 to 2 days in duration, and is a diagnosis of exclusion after ruling out possible organic disorders [10]. Isolated menarche is unusual, with a frequency being less than 10% of that of cases of true sexual precocity or isosexual precocity in girls [10]. Isolated premature menarche is transient and does not affect adult height [10].

The studies on vaginal bleeding in prepubertal girls is still limited [12]. The presence of vaginal bleeding in isolated premature menarche needs early detection to maximize a child’s growth and development in the future. Therefore, this report describes the case of 17-month-old female infant with monthly vaginal bleeding and a diagnosis of isolated premature menarche.

Case Report

A 17-month-old girl presented to our endocrinology obstetrics and gynecology unit with vaginal bleeding every month over the 3 months prior to admission. Her mother stated that the bleeding was about 5 to 10 cc every month. She had no history of abdominal pain, headache, blurred vision, breast enlargement, behavioral changes, and neurological deficits. There was no history of trauma, surgery, seizure, encephalitis, radiation exposure, or pesticide exposure. She was born at term pregnancy without complications. The family history was unknown, and the gestational and perinatal period were unremarkable. The vaginal bleeding events are documented in Table 1.

Physical examination showed a girl with a body weight of 13.5 kg, height of 87 cm (weight-for-age percentile, >97th; length-for-age percentile, >97th, weight-for-length percentile, 85th-97th). She had a normal developmental phenotype. The thyroid gland was not palpable. Her pubertal development according to the Tanner staging system was stage I (A0P0S0). The physical examination revealed normal growth and no dysmorphic features. External genital examination revealed normal female genitalia appropriate for her age. The vulva and vaginal introitus were clean and non-erythematous, with no signs of inflammation, discharge, trauma, bruising, or bleeding at the time of examination. There were no excoriations, lacerations, or signs suggestive of sexual abuse. No foreign body was visualized, and there was no foul-smelling discharge. Abdominal examination revealed no palpable masses in the lower abdomen or pelvis. Breast examination showed no palpable breast tissue (Tanner stage I), and there was no pubic or axillary hair development. The remainder of the systemic examination was unremarkable. This findings, together with the clinical history and subsequent investigations, effectively excluded vulvovaginitis, vaginal foreign body, sexual abuse, and neoplastic causes as potential explanations for the vaginal bleeding.

To investigate several differential diagnoses, we conducted laboratory and radiology examinations to help guide the diagnostic and therapeutic decisions. Table 2 shows the laboratory analysis of this patient. At first, thyroid hormone levels were slightly low, and thyroid-stimulating hormone was slightly elevated. Then, the laboratory findings revealed free thyroxine level of 1.4 ng/dL, thyroid-stimulating hormone level of 5.7 IU/mL, follicle-stimulating hormone level of 4.67 IU/mL, luteinizing hormone less than 0.07 IU/mL, estradiol level of 20.66 pg/mL, prothrombin time of 14.0 seconds, international normalized ratio of 1.01, and activated partial thromboplastin time of 30.7 seconds. Platelet aggregation revealed hyperaggregation in adenosine diphosphate (ADP) at concentrations of 1 μM (24.6%), 2.5 μM (90%), 5 μM (90.3%), and 10 μM (89.1%). Platelet function testing demonstrated thrombocyte hyperaggregation. The patient did not exhibit clinical features of infection or thrombotic events. She was afebrile, and inflammatory markers were within normal limits. No underlying infectious, inflammatory, or hematologic disorder was identified. Given the absence of supporting clinical findings, thrombocyte hyperaggregation was considered a transient and incidental laboratory finding.

Several auxiliary examinations were done, such as the thyroid scintigraphy, which showed thyroid lobes were not enlarged and captured distributed radioactivity. Ultrasonography revealed the fundus-to-cervix ratio was 2: 1, and there was no cyst or mass identified. These findings were consistent with the age of puberty, as shown in Figure 1. To aid in the differential diagnosis of hypothyroidism, bone age was assessed using bilateral hand radiographs, as shown in Figure 2. According to the Greulich and Pyle atlas, bone age was estimated at 1 year and 6 months, compared with a chronological age of 2 years and 1 month. The 6-month difference was considered to be within the normal range.

Based on the investigation results described above, including bone age assessment and measurements of basal serum luteinizing hormone, follicle-stimulating hormone, 17-hydroxyprogesterone, and thyroid function, bone age was consistent with chronological age, and all hormonal values were within prepubertal or normal reference ranges. In the absence of secondary sexual characteristics, accelerated growth, or advanced bone maturation, there was no clinical evidence of activation of the hypothalamic-pituitary gonadal axis.

In this patient, repeated episodes of vaginal bleeding occurred without breast development and pubic or axillary hair growth, and growth velocity remained appropriate for age. There was no evidence of activation of the hypothalamic-pituitary-gonadal axis on hormonal evaluation, and bone age was not advanced. Pelvic ultrasonography demonstrated a prepubertal uterus and ovaries without cysts, masses, or other abnormalities. Local causes of vaginal bleeding, including vulvovaginitis, vaginal foreign body, trauma, sexual abuse, and neoplastic processes, were excluded based on history, physical examination, and imaging findings. In the absence of pubertal progression or an identifiable pathological cause, the diagnosis of isolated premature menarche was established.

After the examination, the patient was diagnosed with isolated premature menarche as a diagnosis of exclusion. The patient was treated with tranexamic acid 200 mg administered 3 times daily, which was effective in controlling the bleeding and correcting the hormonal imbalance. The patient showed a good clinical response, and the prognosis was favorable.

Discussion

Young girls presenting with recurrent vaginal bleeding in the absence of secondary sexual characteristics, normal growth velocity, prepubertal gonadotropin levels, and no progression to true precocious puberty are considered as cases of isolated premature menarche, as presented in this case. Our findings were in line with those of a study reporting isolated premature menarche as a rare and incompletely understood variant of early pubertal development, with most evidence derived from case reports and small case series [13].

Recurrent vaginal bleeding is a rare condition in prepubertal girls and considered a unique case. Cyclical bleeding that lasts for 2 to 5 days should be considered as isolated menstruation. The phenomenon of menstrual-like bleeding before thelarche is very rare and has been defined as premature menarche analogous to premature thelarche and pubarche. These conditions lead to an incomplete form of precocious puberty, since no other signs of puberty are present [14]. Precocious puberty is characterized by early onset of pubertal changes, acceleration of growth velocity, inappropriate body appearance, psychological behavioral abnormalities, and rapid bone maturation that often result in reduced adult height in the future [15]. All of these findings are related to changes in hormonal balance. Endocrinological examinations are needed, including gonadotropins hormones (follicle-stimulating hormone, luteinizing hormone) and sex steroid. Follicle-stimulating hormone and luteinizing hormone are suppressed in peripheral precocious puberty at prepubertal levels [6].

Precocious puberty in girls should be confirmed by an increase in gonadotropin or sex steroid levels, accelerated somatic development, and advanced bone age. Peripheral precocious puberty is independent of gonadotropin secretion, and there is no activation of the hypothalamic-pituitary-gonadal axis. The sources of sex steroids are exogenous and/or endogenous [6,16]. Therefore, the evaluation of vaginal bleeding in a prepubertal child requires exclusion of endocrine causes and precocious puberty through the assessment of bone age, basal gonadotropins, adrenal steroid levels, and thyroid function. In cases in which basal gonadotropin levels remain within the prepubertal range, and there is no clinical or radiological evidence of pubertal progression, isolated premature menarche can be diagnosed as a diagnosis of exclusion. In the present case, normal bone maturation, prepubertal basal hormone levels, appropriate growth velocity, and the absence of secondary sexual characteristics support this diagnosis and make central precocious puberty unlikely; therefore, a gonadotropin-releasing hormone (GnRH) stimulation test was not performed [6,17].

Similar to a recent study describing infants and toddlers with episodic vaginal bleeding and prepubertal hormonal profiles, this case emphasizes the benign and self-limited nature of the condition. More recent reports, including those by Berberoglu et al, have reinforced that isolated premature menarche is characterized by normal bone age, lack of breast development, prepubertal pelvic ultrasonography findings, and absence of hypothalamic-pituitary-gonadal axis activation. In these patients, pelvic imaging typically demonstrates a prepubertal uterus and may vary without cysts or masses, and long-term follow-up reveals no progression to central precocious puberty [6]. Teilman et al further noted that conservative management with observation alone is sufficient for most patients, provided careful follow-up is ensured [18].

Isolated premature menarche is characterized by recurrent vaginal bleeding in prepubertal girls in the absence of other signs of pubertal development and is a diagnosis of exclusion. Isolated premature menarche presents with cyclical vaginal bleeding in the absence of breast and pubic hair development [10]. Unlike central precocious puberty, isolated premature menarche is not associated with breast development, pubertal progression, accelerated growth velocity, or advanced bone age. Endocrine evaluation typically does not demonstrate activation of the hypothalamic-pituitary-gonadal axis, and pelvic imaging reveals prepubertal reproductive organs. In the present case, the absence of secondary sexual characteristics, normal growth pattern, lack of hormonal activation, and normal pelvic imaging findings support the diagnosis of isolated premature menarche. After exclusion of local, systemic, and neoplastic causes of vaginal bleeding, this diagnosis was established. Recognition of isolated premature menarche is important to avoid unnecessary investigations and interventions while ensuring appropriate clinical follow-up. Most cases tend to have few episodes of menstruation that stop spontaneously, and others can continue to have periods into adulthood [10]. Isolated premature menarche is related to the increased sensitivity of the endometrium to estrogens that would be expected to result in endometrial thickening. [1]. In the present case, the child had no axillary or pubic hair [19,20]. Breast enlargement did not occur, likely because the menstrual-like bleeding appeared earlier than usual, even before breast development, and may be related to premature activation of the hypothalamic-pituitary-gonadal axis. In precocious puberty, the ovaries can be stimulated without a complete hormonal cascade, which causes variability in the timing and sequence of pubertal development [14]. Isolated premature menarche is benign and self-limiting, although it can be a source of concern for the child and her family [1].

Premature adrenarche is closely associated with an increase in adrenal androgens due to premature maturation of the zona reticularis of the adrenal cortex in girls and boys before the ages of 8 and 9 years, respectively [21]. Adrenal glands produce hormones such as cortisol and aldosterone that can be converted into sex steroid hormones such as androgen and estrogen. Thrombocyte membranes absorb sex steroid hormones then modify surface membrane permeability. Sex steroid hormones interact not only with plasminogen and fibrinogen, but also with fibrinolytic inhibitors. It has been documented that testosterone increases plasma prostaglandin concentrations. Several studies have shown that ADP, often used at specific micromolar concentrations, is adequate to induce platelet aggregation. In the present case, platelet aggregation was assessed using ADP at concentrations of 10 μM, 5 μM, 2.5 μM, and 1 μM. In in vitro experiments, the addition of androgens influences arachidonic acid pathways, which in turn induce platelet aggregation.

Testosterone can influence platelet aggregation, enhancing thrombus formation and potentially contributing to increased mortality [21]. Thrombocyte hyperaggregation is most commonly described as a reactive and transient laboratory abnormality, often associated with inflammatory or infectious conditions, and is not a recognized cause of vaginal bleeding or isolated premature menarche. In the present case, the absence of clinical infection and normal inflammatory markers suggest that thrombocyte hyperaggregation was an incidental finding without causal relevance to the patient’s vaginal bleeding. Consequently, this laboratory abnormality was not considered contributory to the diagnosis, which remained isolated premature menarche established by exclusion of other diagnosis [22,23].

The present case closely resembles previously reported cases in terms of age at presentation, recurrent menstrual-like bleeding, absence of secondary sexual characteristics, normal bone maturation, and prepubertal pelvic imaging. Consistent with the literature, no endocrine or structural pathology was identified, and the clinical course was favorable. This comparison supports classifying isolated premature menarche as a diagnosis of exclusion with a benign prognosis, underscoring its importance in distinguishing the condition from true puberty and avoiding unnecessary interventions.

Conclusions

Children with menstrual-like vaginal bleeding in the prepubertal period should always undergo a systematic and comprehensive evaluation to differentiate isolated premature menarche from other pathological causes. Recognizing findings indicative of this benign condition is important to avoid unnecessary interventions and to ensure appropriate follow-up.