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Hypothalamic–pituitary–gonadal axis. Shown is the hypothalamic–pituitary–gonadal axis, which regulates the production of the sex hormones estradiol and testosterone. Green arrows indicate stimulatory actions, and red lines indicate inhibitory actions. Abbreviations: GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone; PRL, prolactin.


Menstrual Cycle

  • Follicular phase (day 0–13): From the onset of menses to the LH surge. The follicle develops during this phase. Estradiol inhibits FSH and LH during this phase and promotes endometrial healing. Rising estradiol causes menstruation to end.

  • Ovulation (day 14): The dominant follicle secretes estradiol. Estradiol increases above a level such that it now positively feeds back to increase LH/FSH, and the resultant LH surge causes ovulation.

  • Luteal phase (day 15–28): The corpus luteum produces estrogen. If the corpus luteum is not fertilized, it involutes and progesterone production declines. If it is fertilized, the zygote secretes bHCG, which sustains the corpus luteum.


Concentrations of hormones throughout the menstrual cycle. The menstrual cycle is regulated by the complex interactions of four hormones: estradiol (a form of estrogen), progesterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). There are three phases, as described in the text.


Primary amenorrhea

  • Definition: Absent menses at age 15 yr

  • Etiologies:

    • - Genetic (50%): Turner’s syndrome (XO karyotype) – patients may have a webbed neck, coarctation of the aorta. Diagnosis: High FSH, check karyotype.

    • - Hormonal (35%): Low sex hormones due to excessive exercise, anorexia, craniopharyngioma. Diagnosis: Low FSH, consider brain MRI.

    • - Anatomic/structural (15%): Müllerian agenesis, transverse vaginal septum, imperforate hymen. Diagnosis: Transvaginal ultrasound.

Secondary amenorrhea

  • Definition: Absent menses for >3 months in women with previously regular menstrual cycles or >6 months if irregular menstrual cycles

  • Etiologies:

    • - Pregnancy (always rule out first!)

    • - Ovarian: Polycystic ovarian syndrome (PCOS), ovarian failure (↑FSH)

    • - Hypothalamic: Stress, exercise, systemic illness, and weight loss can result in functional hypothalamic amenorrhea (disruptions in pulsatile release of hypothalamic GnRH)

    • - Pituitary: Prolactinoma (↑prolactin), empty sella syndrome

    • - Endocrine: Hypo/hyperthyroidism, diabetes, obesity (normal FSH/LH but anovulation because progesterone dysregulation)

    • - Uterine: Asherman’s syndrome post dilation and curettage (D&C)

  • Diagnosis: Urine pregnancy test, FSH, LH, prolactin, estradiol, TSH. Abnormal findings will guide management. If normal: Progesterone challenge can further assess estrogen status and functional anatomy. If progesterone challenge provokes menses, then the patient has a normal estrogen state; consider hyperandrogenism.

Hyperandrogenism syndromes

Polycystic Ovarian Syndrome (PCOS)

  • Symptoms: Weight gain, male pattern baldness, acne, oligomenorrhea. Risk endometrial cancer due to unopposed estrogen.

  • Criteria: Need two of the following: 1) Oligomenorrhea/anovulation; 2) Clinical/biochemical evidence of hyperandrogenism (hirsutism, acne); 3) Polycystic ovaries on pelvic ultrasound


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