Delayed menarche with normal pubertal growth

The Case

A 14-year-old female presents for a wellness visit. On history, she is noted to not have started her menstrual cycle but on physical exam has significant breast and pubic hair development since the age of 10 years.

Pertinent review of systems findings include that the patient has denied appetite changes and unexpected weight changes. She has no fevers, no night sweats, no headaches, no nipple discharge, no tachycardia, no palpitations, no constipation, no hair loss, no cold or heat intolerance, and no abdominal pain, nausea, vomiting, or diarrhea. She reports no cyclic pelvic or abdominal pain, vaginal bleeding, vaginal discharge, or vaginal pain; no eating disorder; and no increase in physical activity. The patient also does not exercise regularly.

History

The patient does not have any significant past medical history. Her family history includes the mother, who started her menstrual cycle at age 12 years, and her sister, who started her menstrual cycle at age 10 years. The father is deceased from un known causes. The patient currently is not taking any medication.

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Her social history includes living with her mother and older sister, and she is doing well in school at the appropriate grade level. She denies alcohol, drugs, and tobacco use. She denies sexual activity currently or in the past. She denies depression and anxiety, and has no history of mental illnesses. She is not concerned with not having a period.

Physical exam

The patient’s blood pressure (BP) is 147/92 mm Hg; pulse is 72 beats per minute; respiratory rate is 16 breaths per minute; and her oral temperature is 98.2°F. Her weight is 102.4 kg (225 lb 12 oz), which puts her at the 100th percentile for weight for age (see Growth Chart 1); her body mass index (BMI) is 30.91 kg/m², which puts her at the 97th percentile for BMI (see Growth Chart 2); and her height is 1.82 m (5 ft 11.65 in), in the 100th percentile for stature for age (see Growth Chart 3).

The patient is oriented to person, place, and time. She appears well developed and well nourished, and is noted to have elevated blood pressure. Head, eyes, nose, and throat exams are normal, as are lungs, abdominal, and cardiovascular exams. No hair loss or hirsutism are noted. Her skin is warm and dry. No acne is noted. A dark discoloration and velvety thickening of the skin is noted at the neck region consistent with acanthosis nigricans. The patient is Tanner stage IV for breast and pubic hair development.

At this stage, a workup is initiated to rule out organic causes for delayed menarche in a teenaged girl with secondary sexual development.

Differential diagnosis

Amenorrhea is the absence of menstruation attributed to primary or secondary conditions. The most common cause of amenorrhea is pregnancy. Primary amenorrhea is defined as absence of menarche by age 16 years with normal pubertal growth and sexual development, or a girl who has not started menstruation within 3 years of the first signs of puberty.^1,2 There are many causes associated with primary amenorrhea such as anatomic defects, pituitary causes, endocrine gland disorders, and congenital abnormalities. Secondary amenorrhea is defined as a delay of at least 3 periods in a row with previous regular menses for 3 months or irregular menses for 6 months.² Causes of secondary amenorrhea may include stress, eating disorders, hyperprolactinemia, chemotherapy, or irradiation, among others (Table 1).³

This patient is considered obese based on her current BMI of 30.91 kg/m², which is at the 97th percentile, and current weight of 102.4 kg, which is at the 100th percentile based on weight for age. The risk of developing hyperandrogenemia, hyperinsulinemia, and/or anovulation is highest in obese subjects.⁴ On physical exam, acanthosis nigricans is noted at the neck region. Acanthosis nigricans can be evidence of insulin resistance as well as androgen excess.⁵ Among adolescent patients, obesity has been associated with the development of hyperandrogenemia and hyperinsulinemia.⁶

Further investigation

Laboratory tests are ordered for this patient to rule out the main causes of primary amenorrhea (Table 2). Laboratory findings are significant for an elevated free and total testosterone with hyperinsulinemia, as well as an increase in the luteinizing hormone (LH) to follicle stimulating hormone (FSH) ratio of 6.9:4.9, which is approximately 2:1.

At follow-up 4 weeks later, lab results were discussed with the patient and parent. The patient has continued doing well without cyclic pelvic pain, and still has no periods. Review of systems and the physical exam remained the same with a continued elevated BP of 144/86 mm Hg. The individual FSH and LH levels were within normal range, which ruled out ovarian failure. However, there was a slight increase in the LH to FSH ratio. The increase in the LH may cause an increase in the testosterone level, which was present in her laboratory findings. Causes for elevated testosterone levels include Cushing syndrome, ovarian tumors, thyroid disorders, adrenal tumor, ovarian tumor, or hyperandrogenism. Abnormal levels of prolactin (PRL) and thyroid stimulating hormone (TSH) can cause amenorrhea resulting from hyperprolactinemia or thyroid gland dysregulation, respectively, which were both within normal limits for this patient, indicating these were not the cause for this patient’s primary amenorrhea.⁷

At initial presentation, a pelvic ultrasound had been ordered because it could confirm the presence or absence of a uterus and identify structural abnormalities of the reproductive tract organs. This patient’s ultrasound confirmed the presence of a postmenarchal uterus with peripherally placed follicles throughout both ovaries (Figure 1A and 1B).

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At this point, the girl’s physicians had confirmed hyperandrogenism attributed to an elevated free and total testosterone level, and a slightly elevated LH to FSH ratio of 2:1. Primary amenorrhea was present with developed secondary sexual characteristics to include Tanner stage IV for breast and pubic hair development in this obese 14-year-old patient for the last 4 years. The patient showed evidence of hyperinsulinemia based on laboratory finding of elevated insulin and physical exam finding of acanthosis nigricans. Finally, her ultrasound demonstrated a postmenarchal female with polycystic ovaries.

Based on the above evidence, the diagnosis was made of primary amenorrhea secondary to polycystic ovarian syndrome (PCOS; Table 3).

Diagnosis

Polycystic ovarian syndrome is a heterogeneous syndrome that usually presents during adolescence with unexplained hyperandrogenism and persistent anovulatory menstrual abnormality.⁸ In adolescents, it is characterized by hyperandrogenism and ovulatory dysfunction or abnormal uterine bleeding patterns. The exact etiology is unknown. It is one of the more common causes of elevated testosterone levels that was noted in this patient.

Patients may present with acne, hirsutism, deepening of the voice, and androgenic alopecia, if hyperandrogenism is associated with their symptoms.⁸ An accurate diagnosis is a challenge because symptoms for PCOS can vary with race, age, weight, and medications. Adolescent patients pose particular diagnostic problems because characteristics of normal puberty often overlap with signs and symptoms of PCOS.

There is currently a single indicator for hyperandrogenemia, which is identified as an elevated serum free testosterone caused by the bioactive portion of the serum testosterone that is the free fraction.⁹ The patient in this case presented with lack of menarche by more than 3 years after the onset of breast and pubic hair development and elevated free testosterone levels, which meets the criteria (Table 3).

Epidemiology

Polycystic ovarian syndrome is a common endocrine system disorder affecting 5% to 10% of women of reproductive age.⁷ In the United States, PCOS is the single most common endocrine cause of anovulatory infertility and is a risk factor for metabolic abnormalities.¹⁰

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In a cross-sectional study with adolescent girls, it was determined that the majority of patients with PCOS were also diagnosed with hyperandrogenism and/or oligoanovulation: 69.6% and 67.6%, respectively.¹⁰ The study also associated PCOS with increased weight, demonstrating that adolescents with PCOS were substantially more likely to be moderately or extremely obese than those without PCOS.^10,11

Clinical studies suggest that the metabolic risk associated with PCOS is mostly due to obesity and that it does not independently increase the metabolic risk of adolescents.⁹

Treatment and management

Treatment for PCOS is a systematic approach directed at the underlying cause. The treatment also can be initialized depending on the patients’ complaints and goals. The priority in the adolescent with PCOS is treating menstrual irregularity and cutaneous manifestations of hyperandrogenism. Once PCOS is established in the adolescent, it is critical that screening for metabolic abnormalities is initiated.¹²

Combined oral contraceptives (COCs) are the first-line medical treatment for adolescents because they normalize endometrial cycling, protecting against endometrial carcinoma and inhibiting ovarian function, and thereby normalizing serum androgens.⁴ Oral contraceptive pills (OCPs) decrease the LH levels and decrease androgen synthesis while increasing sex hormone-binding globulin levels and testosterone-binding globulin levels, thereby decreasing free testosterone.⁵

Progesterone monotherapy is an alternative to COCs for those who are at risk for thromboembolic events or with contraindications for COCs. The disadvantage to this alternative is that irregular bleeding may persist and androgens are not well suppressed.¹²

Lifestyle modifications are crucial in eliminating comorbidities related to obesity and insulin resistance. Diet, medication compliance, and exercise have shown 50% probability of improvement in menstrual cyclicity.¹²

Discussion

The Endocrine Society’s clinical guidelines define the appropriate criteria for the diagnosis of PCOS in the adolescent. These include an abnormal uterine bleeding pattern for age or gynecologic age persistent for 1 to 2 years (Table 3).¹³ Evidence of hyperandrogenism is also part of the diagnostic criteria and it includes persistent elevated testosterone, hirsutism, or acne.¹²

Until the Endocrine Society's criteria were established, there were only the Rotterdam criteria for the diagnosis of PCOS that stated that 2 of the following 3 conditions should be present in women with PCOS:

1. Absence of ovulation, irregular menstrual periods, or amenorrhea.

2. Elevated levels of androgens (acne, excess body or facial hair).

3. Confirmed polycystic ovaries.

These criteria were problematic in adolescents because oligomenorrhea, acne, and multifollicular ovary morphology normally can be present in adolescent girls.¹³

An ultrasound should not be used as a diagnostic criterion in adolescents because polycystic morphology is a common finding in the adolescent age group. An ultrasound should be used as a supportive method to help confirm the presence or absence of a thickened uterus and identify structural abnormalities.¹ Pelvic ultrasounds are commonly ordered in the adult patient with PCOS to determine thickened uterus, ovarian volume, and number of follicles present. In the adolescent, increased ovarian volume and polycystic morphology is a common presentation outside of PCOS.

Case resolution

This patient met the criteria for PCOS based on the Endocrine Society’s clinical guidelines for the diagnosis of PCOS in adolescents.

At this time, the decision was made to start with a progesterone challenge test to confirm anovulation versus inadequate estrogen or outflow tract obstruction. Positive withdraw bleeding confirms that there is a lack of ovulation. If the patient had no vaginal bleeding, then this could indicate inadequate estrogen or outflow tract obstruction. Medroxyprogesterone 10 mg daily was ordered for 10 days.

Prior to treatment with OCPs, a bone age radiograph was also ordered to confirm that the patient had reached physical growth and development. It was obtained to assess whether the epiphyses had closed, and to ensure that the bone age correlated with the patient’s chronological age. Based on her height, weight, and sexual characteristics, her physicians did not anticipate a delay in bone age.^11,13 Bone age needs to be considered when hormones such as estrogen are prescribed because the growth plate closes sooner in response to estrogen.

The radiograph results confirmed that the patient’s bone age was consistent with her actual physical growth and development (Figure 2).

At the 2-week follow-up, the progesterone challenge test was completed and the patient had vaginal bleeding. She was otherwise doing well. The option of OCPs was discussed and the decision was made to start the contraceptives. A discussion of diet and exercise as a way to normalize her menstrual cycles was initiated as well.

The patient continued to do well on OCPs and continued with regular periods. Over the course of several months, and with appropriate lifestyle modifications, she lost 10 pounds.

REFERENCES

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11. Nezi M, Christopoulos P, Paltoglou G, et al. Focus on BMI and subclinical hypothyroidism in adolescent girls first examined for amenorrhea or oligomenorrhea. The emerging role of polycystic ovary syndrome. J Pediatr Endocrinol Metab. 2016;29(6):693-702.

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13. Witchel SF, Oberfield S, Rosenfield RL, et al. The diagnosis of polycystic ovarian syndrome during adolescence. Horm Res Paediatr. 2015;83(6):376-389.