Central regulation: hypothalamus and pituitary gland
The menstrual cycle is initiated in the hypothalamus, where gonadotropin-releasing hormone (GnRH) is synthesized. This hormone reaches the adenohypophysis via the portal system and stimulates the production of two tropic hormones: luteinizing hormone (LH) and follicle-stimulating hormone (FSH).
A key feature of GnRH secretion is its pulsatile nature:
- Pulses every 60 minutes predominantly stimulate LH secretion.
- Pulses every 120 minutes predominantly stimulate FSH secretion.
- Constant (non-pulsatile) secretion leads to receptor desensitization and cessation of pituitary response.
Above the hypothalamus stands a master regulator—the neuropeptide kisspeptin, which is sensitive to metabolic and stress status. Decreased levels of leptin and insulin in body weight deficiency, hyperinsulinemia in obesity, and high cortisol levels in chronic stress suppress kisspeptin expression and, consequently, GnRH secretion.
Ovarian cycle: follicle, ovulation, corpus luteum
In the ovary, each follicle contains an oocyte surrounded by two types of cells:
- Theca cells, under the action of LH, synthesize androgens (including testosterone).
- Granulosa cells, under the action of FSH with the help of the enzyme aromatase, convert androgens into estradiol (E2).
As the dominant follicle grows, LH receptors appear in granulosa cells. When a high level of estradiol is reached, the type of feedback changes: instead of inhibition, estradiol stimulates the pituitary gland, forming the LH surge, which triggers ovulation.
Following ovulation, granulosa cells undergo luteinization to form the corpus luteum, which secretes progesterone. Progesterone suppresses the hypothalamus and prepares the endometrium for implantation by promoting spiral arteriole growth and glandular secretion. In the absence of pregnancy, the corpus luteum regresses, the spiral arterioles spasm, and the endometrium is shed, resulting in menstruation.
Disorders at the hypothalamic and pituitary levels
Disruptions in central regulation are a frequent cause of amenorrhea:
- Functional hypothalamic amenorrhea: decreased GnRH secretion in body weight deficiency, excessive physical exertion, chronic stress, obesity, and metabolic syndrome.
- Kallmann syndrome: genetically determined absence of GnRH-secreting neurons, often combined with anosmia.
- Tumors, infections, and infiltrative processes of the hypothalamus.
- Hyperprolactinemia (prolactinoma, use of antipsychotics): prolactin suppresses kisspeptin and LH/FSH secretion.
- Sheehan syndrome (postpartum pituitary infarction) and empty sella syndrome: loss of gonadotropic function.
Disorders at the level of the ovaries, uterus, and adrenal glands
Ovarian causes:
- Polycystic ovary syndrome (PCOS). Hyperinsulinemia decreases SHBG levels, increasing the free testosterone fraction. Androgens destroy progesterone receptors in the hypothalamus, disrupting negative feedback. GnRH is secreted at a frequency of once an hour, which elevates LH, stimulates theca cells, increases androgen synthesis—forming a vicious circle and anovulation.
- Premature ovarian insufficiency: depletion of the follicular reserve, verified by a low anti-Müllerian hormone (AMH) level.
- Aromatase deficiency: inability to synthesize estradiol.
- Gonadal dysgenesis, Turner syndrome.
Uterine causes: Asherman's syndrome (intrauterine synechiae after abortions and curettage), Mayer–Rokitansky–Küster–Hauser syndrome (uterine and vaginal aplasia), endometrial insensitivity to hormones.
Adrenal causes include: congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, leading to 17-OH-progesterone accumulation and a shift in steroidogenesis toward androgens; Cushing's syndrome with hypercortisolemia suppressing kisspeptin. Hypothyroidism also leads to menstrual cycle disorders.
Laboratory diagnostics
Baseline evaluation includes determining LH, FSH, estradiol, progesterone on day 21 of the cycle, testosterone, DHEA-S, 17-OH-progesterone, AMH, prolactin, and TSH.
- Low LH and FSH: hypogonadotropic hypogonadism (functional hypothalamic amenorrhea, Kallmann syndrome, Sheehan syndrome).
- LH elevated, FSH normal; LH/FSH > 2: characteristic of PCOS.
- High LH and FSH: primary ovarian insufficiency or ovarian resistance.
- Low AMH: depletion of the follicular reserve; high AMH: supports the diagnosis of PCOS.
- Low estradiol: ovarian insufficiency or aromatase deficiency.
- Low progesterone on day 21: anovulatory cycle.
- High testosterone with normal DHEA-S: ovarian source (PCOS); high DHEA-S and 17-OH-progesterone: adrenal source (CAH).
Key points
- The menstrual cycle is regulated by the hypothalamic-pituitary-ovarian axis with an obligatory pulsatile pattern of GnRH secretion.
- Kisspeptin is the main modulator of GnRH, sensitive to metabolism, leptin, insulin, and cortisol.
- Two-cell theory: theca cells under LH action produce androgens, granulosa cells under FSH action via aromatase synthesize estradiol.
- The LH surge occurs due to the shift from negative to positive feedback at high estradiol levels and triggers ovulation.
- PCOS develops via hyperinsulinemia, decreased SHBG, hyperandrogenism, and loss of hypothalamic sensitivity to progesterone.
- An LH/FSH ratio > 2 and high AMH support the diagnosis of PCOS; high LH and FSH indicate ovarian insufficiency.
- DHEA sulfate and 17-OH-progesterone allow differentiation of adrenal hyperandrogenism (CAH) from ovarian.
- Hyperprolactinemia, hypothyroidism, Cushing's syndrome, and Sheehan syndrome are mandatory endocrine causes to rule out in amenorrhea.