Anovulatory cycle: causes and symptoms

An anovulatory cycle is a menstrual cycle without ovulation and a complete luteal phase. Due to the absence of progesterone, the endometrium is continuously stimulated by estrogens ("unopposed estrogen"), leading to irregular, often heavy, or prolonged bleeding of the AUB-O (abnormal uterine bleeding-ovulatory dysfunction) type and an increased risk of endometrial hyperplasia. In reproductive age, the most common cause is polycystic ovary syndrome (PCOS), but it is important to rule out hyperprolactinemia, thyroid dysfunction, hypothalamic amenorrhea, premature ovarian failure, and others. [1]

Clinically, anovulation presents with oligomenorrhea/amenorrhea, intermenstrual bleeding, and infertility; in some patients, acne, hirsutism, and weight gain (associated with PCOS). Confirmation of ovulation/anovulation relies on luteal phase biomarkers (serum progesterone) and/or ultrasound monitoring of follicle growth/corpus luteum formation. [2]

Management depends on reproductive plans: if there are no plans for pregnancy, the goal is cycle regularization and endometrial protection (progestogens/COCs); if pregnancy is desired, ovulation induction is the goal (letrozole is the first-line drug in patients with PCOS). For secondary endocrine causes, therapy is etiotropic (cabergoline for hyperprolactinemia, pulse GnRH for hypothalamic amenorrhea, etc.). [3]

Epidemiology

Anovulatory cycles are physiologically common in the first 1-2 years after menarche and during perimenopause; during reproductive age, they are less common and are usually associated with pathology. Up to 15-25% of women seeking treatment for infertility experience anovulation, with the majority having PCOS. [4]

PCOS is a leading cause of chronic anovulation and female infertility; current international guidelines from 2023 emphasize the unity of diagnostic approaches and therapeutic priorities (including first-line ovulation induction with letrozole). [5]

In adolescents and young women with functional hypothalamic amenorrhea (energy deficiency, stress, intense exercise), the proportion of anovulation is significant; GnRH pulse therapy and restoration of energy balance demonstrate high rates of restored fertility. [6]

Reasons

The most common causes of anovulation in reproductive age are: PCOS, functional hypothalamic amenorrhea, hyperprolactinemia, thyroid disease, premature ovarian failure; less commonly, drug effects and chronic systemic diseases. Episodic anovulatory cycles are also possible in healthy women. [7]

In PCOS, hyperinsulinemia and insulin resistance enhance ovarian androgenesis and impair dominant follicle growth, leading to chronic anovulation and irregular bleeding. This is a key target for lifestyle interventions and pharmacotherapy. [8]

Hyperprolactinemia suppresses GnRH and FSH/LH secretion, causing anovulation and hypogonadism; cabergoline is preferred for normalizing prolactin and restoring ovulation/fertility. In hypothalamic amenorrhea, pulsatile GnRH administration physiologically "restarts" the ovulatory cycle. [9]

Risk factors

Overweight and insulin resistance are associated with PCOS and anovulation; moderate weight loss (5-10%) improves ovulation frequency and metabolic profile. Energy deficiency, fatigue, and high stress levels are risk factors for functional hypothalamic amenorrhea. [10]

Medications (antipsychotics, opioids, etc.) can cause hyperprolactinemia and anovulation; delayed diagnosis increases the risk of endometrial hyperplasia due to prolonged estrogen stimulation. [11]

Thyroid diseases (hypo-/hyperthyroidism) and premature ovarian failure also disrupt ovulation, requiring an etiotropic approach (levothyroxine/hormone replacement therapy, respectively). [12]

Pathogenesis

The key mechanism in anovulation is the absence of peak LH secretion and rupture of the dominant follicle → no corpus luteum → no progesterone. The endometrium is subject to continuous estrogen stimulation with subsequent unstable decidualization, which clinically manifests as irregular and/or heavy bleeding. [13]

In PCOS, insulin and androgens disrupt folliculogenesis and negative feedback of the hypothalamic-pituitary-ovarian axis, creating a vicious cycle of anovulation. In hyperprolactinemia, prolactin suppresses GnRH neurons; in hypothalamic amenorrhea, energy deficiency and stress reduce the frequency of GnRH "pulses." [14]

Symptoms

Typical complaints: oligomenorrhea (cycles >35 days), amenorrhea, intermenstrual bleeding, menorrhagia/metrorrhagia, infertility. In PCOS, hyperandrogenic signs (acne, hirsutism) are often present, and in hyperprolactinemia, galactorrhea/decreased libido. [15]

In the setting of chronic anovulation, iron deficiency anemia (due to AUB-O), dyspareunia/discomfort and anxiety associated with unpredictable bleeding and fertility problems may occur.[16]

Forms and stages

A distinction is made between: 1) physiological anovulation (postmenarche, postpartum period/lactation, perimenopause), 2) pathological chronic anovulation (PCOS, hypothalamic amenorrhea, hyperprolactinemia, etc.), 3) episodic anovulation in healthy women. In the AUB classifications, this corresponds to AUB-O. [17]

Clinically: asymptomatic (found in infertility) and symptomatic (irregular/heavy bleeding). Severity ranges from rare episodes to severe chronic dysfunction with anemia and a high risk of endometrial hyperplasia. [18]

Complications and consequences

Chronic stimulation of the endometrium with estrogens without progesterone increases the risk of endometrial hyperplasia and (less commonly) cancer; therefore, endometrial protection is a mandatory treatment goal when pregnancy is not planned.[19]

Anovulation is one of the leading causes of female infertility; in PCOS, surgery/medication and appropriately chosen ovulation induction have been shown to improve clinical pregnancy and live birth rates. [20]

Heavy bleeding (AUB-O) leads to iron deficiency anemia and reduced quality of life; acute AUB requires immediate medical management (estrogen, multi-modality COC/progestin regimens, tranexamic acid). [21]

Diagnostics

Confirmation of anovulation. The most practical method is a single mid-luteal progesterone assay: a value >3 ng/ml indicates ovulation has occurred; higher thresholds are used to assess the adequacy of the luteal phase. Ultrasound folliculometry/ovulation signs are also used. [22]

Etiological search. TSH, prolactin; in case of hyperandrogenic signs - total/free testosterone, DHEAS; in case of rare/early onset - 17-OH-progesterone (exclude NK-VGKN). According to indications - FSH/estradiol (suspected POI), metabolic profile (glucose, lipids) in PCOS. [23]

Instrumental. Transvaginal ultrasound (evaluation of the ovaries/endometrium); in case of infertility, HSG as indicated. Endometrial biopsy - in case of prolonged anovulation with AUB, a risk factor for hyperplasia, age ≥45 years or earlier with persistent AUB. [24]

Table 1. Diagnostic guidelines for suspected anovulation

Task	Test	Hint/threshold
Confirm the fact of ovulation	Progesterone in the mid-luteal phase	>3 ng/ml = ovulation occurred; optimum ~7 days before menstruation. [25]
Rule out secondary causes	TSH, prolactin	Correction often restores ovulation. [26]
Hyperandrogenism	Testosterone, DEAS; ±17-OH-progesterone	Diff. with PCOS/NC-CAH. [27]
Risk of endometrial pathology	Endometrial biopsy	In AUB and risk factors/age. [28]

Differential diagnosis

Distinguish anovulatory bleeding (AUB-O) from ovulatory bleeding (AUB-E, etc.) based on history, laboratory (progesterone), and ultrasound data. Rule out pregnancy and structural causes using the PALM-COEIN system (polyps, adenomyosis, fibroids, hyperplasia/cancer). [29]

Hyperprolactinemia (including drug-induced), hypo-/hyperthyroidism, functional hypothalamic amenorrhea, PCOS, and POI are key nosologies requiring etiotropic treatment. [30]

Treatment

If pregnancy is not planned (the goal is the cycle and protection of the endometrium):

• Cyclic progestogens (e.g., 10-14 days/month) or COCs are recommended strategies for the prevention of hyperplasia and control of AUB-O. The choice depends on contraindications and preferences. [31]
• For acute AUB-O: intravenous estrogen, multiple COC/oral progestin regimens, tranexamic acid (according to ACOG). [32]
• Metabolic correction in PCOS (weight loss, physical activity; metformin - according to metabolic indications). [33]

If pregnancy is planned (goal - ovulation/fertility):

• PCOS: Letrozole is the first-line drug for ovulation induction; clomiphene is an alternative. In cases of resistance, gonadotropins/IVF are used; dose/cycle selection is based on current RCT data and the 2023 guidelines. [34]
• Hyperprolactinemia: Cabergoline is preferred over bromocriptine; normalization of prolactin restores ovulation and fertility in most cases. [35]
• Functional hypothalamic amenorrhea: restoration of energy/body weight; in case of resistance - pulse GnRH (SC/pump) as a physiological method with a high frequency of monovular ovulation and pregnancies. [36]
• Thyroid dysfunction/POI: etiotropic therapy (levothyroxine; HRT and reproductive technologies for POI). [37]

Endometrial protection in chronic anovulation is mandatory until pregnancy occurs or when it is delayed; the strategy is selected individually (COCs, progestogens, IUDs with levonorgestrel - outside the scope of infertility). [38]

Table 2. Ovulation induction: who, what and when

Etiology	First line	Alternatives/Next Step	Comments
PCOS	Letrozole	Clomiphene → GT/IVF	Letrozole ↑ovulation/labor vs clomiphene. [39]
Hyperprolactinemia	Cabergoline	Bromocriptine	PRL control → ovulation restoration. [40]
Hypothalamic amenorrhea	Pulse-GnRH	Gonadotropins	Physiological, monofollicular, high efficiency. [41]
Thyroid disorders	Levothyroxine (for hypothyroidism)	-	Correction of TSH normalizes the cycle. [42]

Prevention

Prevention of secondary anovulation includes maintaining a normal body weight, regular physical activity, stress/sleep management, early correction of endocrine disorders, and review of medications that can increase prolactin. These measures reduce the risk of functional ovulation disorders and AUB-O. [43]

For women with PCOS, attention should be paid to modifiable factors (diet, activity), metabolic risk management, and timely ovulation induction when planning a pregnancy. In cases of hypothalamic amenorrhea, energy restoration and a gradual increase in exercise under supervision are important. [44]

Forecast

With the elimination of the cause of anovulation and/or proper ovulation induction, the fertility prognosis is favorable: letrozole has been proven effective for PCOS, cabergoline for hyperprolactinemia, and pulsed GnRH for hypothalamic amenorrhea. Early diagnosis and personalized treatment plan increase the chances of pregnancy and childbirth. [45]

Without treatment, chronic anovulation maintains AUB-O, anemia, and the risk of endometrial hyperplasia/cancer. Cycle regularization with progestogens/COCs and endometrial monitoring significantly reduce these risks and rapidly improve quality of life. [46]

FAQ

• How to confirm whether ovulation occurred?

Have progesterone tested ~7 days before your expected period: >3 ng/ml indicates ovulation; additionally, ultrasound signs/dominant follicle and corpus luteum. [47]

• If periods are rare and irregular, how can I protect the endometrium?

Cyclic progestogens 10-14 days monthly or COCs are standard options for the prevention of hyperplasia and control of AUB-O. [48]

• Which is better for inducing ovulation in PCOS - clomiphene or letrozole?

Current recommendations: letrozole is the first line (higher ovulation/pregnancy/delivery rate); clomiphene is an alternative. [49]

• Is it possible to restore ovulation in case of hyperprolactinemia without surgery?

Yes. Cabergoline effectively normalizes prolactin and restores ovulation in most patients. [50]

• What to do with functional hypothalamic amenorrhea if weight has already normalized, but there is no ovulation?

Consider pulse GnRH therapy (where available): this is a physiological and effective way to restore monofollicular ovulation and fertility. [51]

Epidemiology

According to statistics, 15% of women of reproductive age may have a menstrual cycle without ovulation; 50% of adolescent girls have anovulatory cycles in the first two years after the onset of menstruation.

In young women, 75-90% of anovulation cases are due to polycystic ovary syndrome; more than 13% of cases are due to hyperprolactinemia. Idiopathic chronic anovulation occurs in 7.5% of cases. [52], [53], [54]

Almost 30% of infertility cases are caused by anovulatory cycle. [55]

Causes anovulatory cycle

The ovulatory and anovulatory cycles differ fundamentally: the former is a normal menstrual cycle with alternating phases (follicular, ovulatory, and luteal); the latter is abnormal, without the release of a mature oocyte from the follicle, that is, without ovulation, without the formation and involution of the corpus luteum, and without the release of luteinizing hormone from the pituitary gland.

It's important to keep in mind that an anovulatory cycle can be not only pathological but also physiological. Specifically, it occurs during the first two years after menarche in girls; during a sudden change in climate or severe stress; during lactation after childbirth; after a miscarriage or discontinuing birth control pills; and after age 45 due to fluctuating hormone levels before menopause.

The main causes of a pathological anovulatory cycle are hormonal imbalances, which, in turn, can be caused by:

• polycystic ovary syndrome (PCOS);
• dysfunction of the ovaries in the presence of chronic inflammation - oophoritis;
• hyperanlrogenism;
• excessive production of prolactin by the pituitary gland – hyperprolactinemia;
• hyperestrogenism or, conversely, estrogen deficiency;
• dysfunction of the hypothalamic-pituitary system – gonadotropic insufficiency;
• imbalance of thyroid-stimulating hormones (thyroxine and triiodothyronine) in hyper or hypothyroidism;
• dysfunction of the adrenal cortex (hypocorticism), including its hormonally active tumor - androsteroma.

In addition, an excess of the norm of follicles - multifollicular ovaries - can also cause an anovulatory cycle, since the multifollicular structure of the ovaries prevents the maturation of follicles and, in addition, often leads to PCOS and the associated hormonal imbalance. [56]

For more details, see the publication: Causes, Symptoms, and Diagnosis of Anovulation

Depending on the etiology and hormonal state, specialists distinguish between normogonadotropic normoestrogenic, hypergonadotropic hypooestrogenic and hypogonadotropic hypooestrogenic types of anovulatory cycle. [57]

Risk factors

Factors that significantly increase the risk of a cycle without ovulation include:

• long-term use of oral contraceptives;
• hereditary or acquired insulin resistance leading to metabolic syndrome – with increased production of adrenocorticotropic hormone (ACTH) by the pituitary gland and hyperandrogenism;
• overweight or underweight;
• the impact of frequent stress on hormonal levels;
• excessive physical activity (menstrual irregularities and amenorrhea are part of the so-called triad of female athletes);
• uterine diseases (endometriosis, fibroids, etc.);
• tumors of the ovaries, thyroid and parathyroid glands, pituitary gland or hypothalamus;
• adrenal insufficiency.

Pathogenesis

With all the above-mentioned causes, including polycystic ovary syndrome with damage to their follicular apparatus, the pathogenesis of the absence of ovulation is associated with the fact that hormonal homeostasis is disrupted - the natural balance of sex steroids and gonadotropins: estradiol and estrone, androstenedione and testosterone, luteotropin and follitropin (luteinizing and follicle-stimulating hormones - LH and FSH), progesterone, prolactin, gonadotropin-releasing hormone, which are produced by the ovaries and corpus luteum, the adrenal cortex and the hypothalamic-pituitary system. [58], [59], [60]

For a more detailed understanding of the positive and negative relationships between sex and gonadotropic hormones, please see the following publications:

• Menstrual function
• Hormonal regulation of the menstrual cycle
• Monthly cyclic changes in the female reproductive system
• Ovulation disorder

Symptoms anovulatory cycle

With anovulation, the first signs are menstrual cycle irregularities, with cycles shorter than 21 days or longer than 35 days, or cycle lengths that vary from month to month. Although menstruation may occur during an anovulatory cycle (which many gynecologists consider menstrual-like bleeding), it is less regular and longer. Approximately 20% of women experience no periods, a condition known as amenorrhea, and 40% experience infrequent and short periods (if the intervals between periods increase by more than 35 days, this is defined as oligomenorrhea). [61]

In addition, the following symptoms are noted:

• in the second phase, the basal temperature during an anovulatory cycle does not increase;
• there is spotting in the middle of the cycle;
• weight gain and facial hair growth (often associated with PCOS and hypocorticism);
• Heavy bleeding may occur during an anovulatory cycle, which is associated with insufficient levels of FSH and LH and a deficiency of progesterone —hormones that neutralize the effect of estradiol on the uterine lining. This type of bleeding is called breakthrough estrogen bleeding or metrorrhagia, and can be confused with menstruation.
• Cervical mucus - cervical mucus during an anovulatory cycle may become thicker and thinner for a few days, indicating increased estrogen levels in anticipation of ovulation, but then it becomes thick again.

If you have an anovulatory cycle and breast pain, this indicates low progesterone levels. Approximately 20% of women with ovulation problems do not experience breast pain (mastodynia).

However, in a chronic anovulatory cycle, especially in women with PCOS, the endometrium undergoes hyperplasia, that is, growth and thickening, due to the lack of inhibitory effect of progesterone on the stimulation of the uterine mucosa by estrogen.

Complications and consequences

The main consequences and complications of a cycle without an ovulatory phase include:

• infertility, since pregnancy does not occur after an anovulatory cycle (and even when trying to get pregnant with the help of IVF, a donor egg is used);
• early perimenopause and menopause;
• anemia;
• decreased bone density;
• cancerous degeneration of the endometrium.

Diagnostics anovulatory cycle

It would seem that diagnosing an anovulatory cycle is straightforward in the absence of menstruation or irregular periods. However, this is not always the case. [62]

To diagnose an anovulatory cycle, women undergo blood tests to measure levels of estrogen, progesterone, luteinizing and follicle-stimulating hormones, prolactin, 17a-hydroxyprogesterone, dihydrotestosterone, ACTH, thyroid hormones, and insulin. [63]

Instrumental diagnostics are carried out:

• X-ray of the uterus and ovaries;
• Ultrasound of the pelvic organs and uterus.

When conducting a high-resolution transvaginal ultrasound examination, the anovulatory cycle signs on ultrasound are determined by the absence of visualization of the protrusion into the cortex covering the ovary of the dominant (preovular) follicle and vascularization of its wall (perifollicular vascular perfusion).

The task that differential diagnostics solves based on the results of hormonal tests is to determine the underlying cause of anovulatory disorders. [64 ]

Treatment anovulatory cycle

Treatment of the anovulatory cycle is carried out taking into account the cause.

Medications often prescribed to induce ovulation include estrogen antagonists such as clomiphene (Clomid, Clostilbegyt) or tamoxifen (Nolvadex), and the aromatase inhibitor letrozole (Femara).

In cases of hypothalamic-pituitary system dysfunction, Follitropin alpha (by injection) promotes follicle development and stimulates ovulation – 75–150 IU once daily (during the first seven days of the cycle). This drug is contraindicated in cases of ovarian cysts and hypertrophy, as well as tumors of the hypothalamus, pituitary gland, uterus, or mammary glands. Its side effects include nausea, vomiting, abdominal and joint pain, ascites, and the formation of venous thromboembolism. [65]

Also, the injectable drug Puregon (Follitropin beta) can compensate for the FSH deficiency.

Progesterone analogs Dydrogesterone (Duphaston) and Utrozhestan are used in anovulatory cycles with a deficiency of this hormone to stimulate the synthesis of pituitary gonadotropins (LH and FSH) and the luteal phase. The dosage is determined by the doctor; for example, the daily dose of Utrozhestan is 200-400 mg, taken for 10 days (from the 17th to the 26th day of the cycle). This drug is contraindicated in cases of deep vein thrombosis, liver failure, and breast cancer. Side effects include headache, sleep disturbances, fever, nocturnal hyperglycemia, breast tenderness, vomiting, and intestinal disorders. [66], [67], [68], [69]

In cases of hyperprolactinemia, bromocriptine (Parlodel) is used to reduce prolactin production by the pituitary gland. If the anovulatory cycle is associated with increased production of male hormones by the adrenal glands, corticosteroids are prescribed. [70]

Herbal treatments or phytotherapy for ovulation support are most often aimed at restoring hormonal balance. For this purpose, on the recommendation of a physician, the following may be used: tribulus terrestris herb and seeds; red clover herb and flowers; wild yam root; black cohosh root and rhizomes; flaxseed oil; and evening primrose seed oil. Of particular note are the seeds, fruits, and leaves of a tree-like shrub in the mint family—chasteberry (also known as chasteberry). Extracts from these parts of the chasteberry increase dopamine activity in the brain, which leads to a decrease in prolactin release, as well as a normalization of progesterone and estrogen balance and an increase in LH levels.

Also read the article – Treatment of anovulation

Prevention

You can prevent an anovulatory cycle if you have weight problems: if your body mass index increases, you need to lose excess weight; if you have lost a significant amount of weight, you need to gain the missing kilograms. [71]

For women's health, it's important to maintain a healthy lifestyle and a balanced diet. See: Hormonal Balance Products

Forecast

Considering that ovulation can be restored with the help of appropriate medications, [72] the prognosis for an anovulatory cycle is considered favorable in almost 90% of cases.