Menstrual cycle: hormonal regulation by phases

The menstrual cycle is a recurring biological process that simultaneously involves the brain, ovaries, endometrium, and numerous signaling molecules. It is essential not only for conception but also for maintaining a predictable rhythm of the reproductive system. It is based on the coordinated functioning of the hypothalamus, pituitary gland, ovaries, and uterus. [1]

Hormonal regulation of the menstrual cycle is not limited to estrogen and progesterone. Key roles are played by gonadotropin-releasing hormone, follicle-stimulating hormone, luteinizing hormone, estradiol, progesterone, inhibins, activins, and local ovarian and endometrial signaling systems. This is why any disturbances in nutrition, weight, sleep, stress, thyroid function, prolactin levels, or ovulation can affect menstruation. [2]

The modern understanding of the cycle is based on two parallel models. The first describes events in the ovary: follicle growth, ovulation, and the functioning of the corpus luteum. The second describes events in the uterus: menstrual, proliferative, and secretory remodeling of the endometrium. These processes occur synchronously and are interdependent. [3]

It's also important to remember that the "ideal 28-day cycle" is only an average. Many healthy adults have cycles that are somewhat longer or shorter, and irregularities are especially common in the first years after menarche and during perimenopause due to ovulatory instability. Therefore, cycles should be assessed using modern clinical criteria, not a single standardized template. [4]

The new article focuses not only on physiology but also on practical implications. Below, we examine the cycle initiation, phase changes, the role of the endometrium, normal parameters, causes of hormonal imbalances, and a modern diagnostic algorithm for irregular or abnormally heavy periods. [5]

Where the cycle begins: the hypothalamus, pituitary gland, and ovaries

The highest level of regulation is located in the hypothalamus. It secretes gonadotropin-releasing hormone not continuously, but in pulses. This is crucial: if the signals are rhythmic, the pituitary gland responds with normal secretion of follicle-stimulating hormone and luteinizing hormone; if the rhythm is disrupted, ovulation may be disrupted even in the absence of overt ovarian disease. [6]

The frequency of these impulses changes throughout the cycle. It's typically slower in the luteal phase, accelerates in the follicular phase, and before ovulation, a special neuroendocrine regimen is established, triggering the preovulatory peak of luteinizing hormone. This is why the cycle cannot be explained solely by "hormone levels in the blood" without taking into account their secretory rhythm. [7]

The role of KNDy neurons, associated with kisspeptin, neurokinin B, and dynorphin, is now well understood. They help set the frequency of gonadotropin-releasing hormone impulses and are involved in switching the system between inhibition and stimulation. This is important for clinical practice because functional disruptions at the hypothalamic level, for example due to energy deficiency or chronic stress, can indeed stop ovulation without organic damage to the ovaries. [8]

In response, the pituitary gland secretes follicle-stimulating hormone and luteinizing hormone. The former is primarily needed for follicle growth and selection, while the latter is needed for the final maturation of the dominant follicle, ovulation, and subsequent luteinization. These two hormones do not function separately, but rather as a linked system, dependent on feedback from estradiol, progesterone, and inhibins. [9]

The ovary is not just a "target," but an active participant in regulation. Developing follicles secrete estradiol and inhibin B, while the corpus luteum, after ovulation, secretes progesterone, estradiol, and inhibin A. This allows the ovary to constantly "communicate" to the brain about the phase of the cycle, and it is on this basis that the system restructures the subsequent hormonal program. [10]

Below is a brief diagram of the central hormonal regulation of the cycle. [11]

Level of regulation	Main signals	Main function
Hypothalamus	Gonadotropin-releasing hormone	Sets the rhythm of the cycle through pulsatile secretion
Anterior pituitary gland	Follicle-stimulating hormone, luteinizing hormone	Triggers follicle growth, ovulation and corpus luteum function
Ovary, follicle	Estradiol, inhibin B	Dominant follicle selection and negative feedback
Ovary, corpus luteum	Progesterone, estradiol, inhibin A	Support of the secretory phase of the endometrium
Endometrium	Local prostaglandins, cytokines, growth factors	Implements a response to hormonal signals

Follicular phase: how the follicle grows and why estradiol changes

The first day of menstrual bleeding is considered the first day of a new cycle. At this point, progesterone and estradiol levels are low, so the inhibitory effect on the hypothalamus and pituitary gland is weakened. This allows follicle-stimulating hormone to rise slightly and "recruit" a cohort of follicles ready for further growth. [12]

As the follicles grow, granulosa cells begin to increasingly produce estradiol. Initially, this growth is moderate, but then one follicle gains an advantage and becomes dominant. It is this follicle that continues to develop during a normal ovulatory cycle, while the remaining follicles undergo atresia. [13]

Estradiol does several things during the first half of the cycle. It stimulates endometrial proliferation, increases receptor expression, influences cervical mucus, and simultaneously participates in a subtle feedback loop with the pituitary gland. When estradiol levels are low or moderate, the feedback loop is primarily negative, helping to prevent excessive gonadotropin secretion. [14]

Inhibin B, which is secreted by growing follicles, also plays a key role. It primarily suppresses follicle-stimulating hormone, thereby preventing the system from supporting multiple follicles at once before ovulation. This allows for the physiological selection of a single dominant follicle.

The follicular phase is what typically explains why the overall cycle length varies in healthy individuals. The luteal phase is relatively stable in most individuals, but the maturation of the dominant follicle can take a variable number of days. Therefore, ovulation is not necessarily strictly on day 14, even though this example is often used in teaching. [16]

Below are the key events of the follicular phase.[17]

Follicular phase stage	What's happening
Beginning of the cycle	Progesterone and estradiol fall, follicle-stimulating hormone increases slightly
Early follicular growth	A cohort of follicles is formed
Middle phase	Estradiol and inhibin B increase
Selection of a dominant follicle	One follicle gets an advantage
Late phase	Estradiol becomes high enough to prepare for positive feedback

Ovulation and the Luteal Phase: Why Progesterone Is So Important

Ovulation is triggered not by the random rupture of a follicle, but by a precisely orchestrated hormonal event. When high estradiol levels persist long enough, the system switches from negative to positive feedback, and the pituitary gland responds with a preovulatory surge of luteinizing hormone. This is one of the central mechanisms of the entire cycle. [18]

The peak of luteinizing hormone triggers the final maturation of the oocyte, rupture of the mature follicle, and the onset of luteinization of the granulosa cells. After the egg is released, the remnants of the follicle transform into the corpus luteum. This corpus luteum now functions as a temporary endocrine gland and begins actively producing progesterone. [19]

Progesterone is the main hormone of the second half of the cycle. While estradiol primarily builds and thickens the endometrium, progesterone shifts it into a secretory state, preparing the lining for potential implantation. Under its influence, the structure of the glands, the vascular pattern, and the local immune environment of the endometrium change. [20]

The luteal phase is typically more stable in duration than the follicular phase. According to the American Society for Reproductive Medicine, the average luteal phase length is about 14 days, with normal variation being approximately 11-17 days. This explains why, in individuals with varying cycle lengths, the day of menstruation varies primarily due to differences before ovulation rather than after. [21]

If pregnancy does not occur, the corpus luteum gradually regresses, progesterone and estradiol levels fall, and the endometrium loses hormonal support. It is this drop in steroids that triggers the next menstruation, not simply the "onset of day 28." Therefore, menstruation is the end of the luteal phase, with no implantation. [22]

Below is a diagram of ovulation and the luteal phase.[23]

Stage	Leading hormonal shift	Biological result
Preovulatory period	Long-term high estradiol	Positive feedback
Ovulatory peak	A sudden surge of luteinizing hormone	Oocyte release
Early luteal phase	Formation of the corpus luteum	Increase in progesterone
Mid-luteal phase	High progesterone	Secretory transformation of the endometrium
End of cycle without pregnancy	Regression of the corpus luteum	A drop in progesterone and the onset of menstruation

The Endometrium and Menstruation: What Happens in the Womb Every Month

The endometrium is not a passive "lining" of the uterus, but a highly dynamic tissue that undergoes destruction, restoration, growth, and differentiation each cycle. During the proliferative phase, under the influence of estradiol, it thickens, cells actively divide, glands elongate, and the vascular network is restructured. This creates the foundation for subsequent secretory transformation. [24]

After ovulation, progesterone alters the functional program of the endometrium. The glands begin secreting, the stroma becomes more specialized, and preparation for possible implantation intensifies. Essentially, the endometrium switches from growth mode to functional readiness mode. [25]

If pregnancy does not occur, a decrease in progesterone triggers a cascade of local events. Prostaglandin production increases, the tone of the spiral arteries changes, and episodes of ischemia, necrosis, and detachment of the functional layer occur. Menstrual pain is also associated with this: prostaglandins enhance myometrial contractions and vascular changes. [26]

Menstruation, however, is not simply a traumatic bleeding event. Modern reviews emphasize that the endometrium has a unique ability to rapidly and scarlessly regenerate. After the functional layer is shed, epithelial reparation is initiated, local progenitor cells and growth factors are activated, allowing the mucosa to recover for the next cycle. [27]

This is why ovulation disorders so dramatically alter bleeding patterns. When ovulation is absent, a full luteal phase and sufficient progesterone influence do not occur. As a result, the endometrium can remain under the influence of estrogen for a long time without normal secretory transformation, making bleeding irregular, unpredictable, and often heavier. [28]

Below is a comparison of the endometrial phases and the leading hormones. [29]

Endometrial phase	Leading hormonal conditions	What's happening in the tissue?
Menstrual	Decrease in progesterone and estradiol	Rejection of the functional layer
Early proliferative	Estradiol increase	Beginning of mucosal restoration
Late proliferative	High estradiol	Endometrial thickening
Secretory	Progesterone after ovulation	Preparing for implantation
Premenstrual	Regression of the corpus luteum	Prostaglandins, ischemia, onset of menstruation

What is considered a normal cycle and when is irregularity still acceptable?

Modern assessment of the menstrual cycle is based not on a single number, but on four parameters: frequency, regularity, bleeding duration, and volume. According to clinical definitions by FIGO and ACOG, a normal cycle in adults is typically considered to be 24-38 days long, with bleeding up to 8 days and a fairly predictable recurrence. Any deviation in these parameters requires clinical evaluation. [30]

Normal blood loss volume is difficult to measure in everyday life, so clinical assessments focus more on the subjective impact on quality of life, the presence of clots, the need for frequent changes of hygiene products, and signs of iron deficiency. A threshold of over 80 milliliters is traditionally used for research, but in real-life practice, bleeding severity is assessed primarily by symptoms and consequences, rather than by formal milliliter counts. [31]

During adolescence, cycle variability is greater. ACOG notes that in the first years after menarche, cycles are often anovulatory, with a typical range of approximately 21-45 days, with most cycles becoming closer to the adult range of 21-34 days by the third year after menarche. This is important because not all adolescent irregularities indicate a medical condition, but excessively infrequent or very heavy periods still require evaluation. [32]

During perimenopause, on the contrary, irregularities become more frequent again due to fluctuations in ovulation and depletion of the follicular reserve. The World Health Organization notes that with age, cycle length and regularity naturally change, and during perimenopause, periods can become longer, shorter, less frequent, more frequent, heavier, or lighter. However, at this age, it is especially important not to attribute any atypical bleeding solely to "hormones" without assessing the risk of hyperplasia and other endometrial pathologies. [33]

The practical conclusion is simple: the concept of normal depends on age and reproductive stage, but bleeding that is too infrequent, too frequent, too prolonged, intermenstrual, or that changes drastically should not be considered normal without examination. This is especially important if there is anemia, pain, infertility, galactorrhea, severe acne, hirsutism, sudden weight loss, or a suspicion of pregnancy. [34]

Below are guidelines for normal and warning signs. [35]

Parameter	Usually normal in adults	When an analysis of the cause is already necessary
Cycle frequency	24-38 days	Less than 24 days or more than 38 days
Duration of bleeding	Up to 8 days	More than 8 days
Regularity	Relatively predictable	Expressedly unpredictable
Volume	Does not impair quality of life and does not lead to anemia	Very heavy bleeding, clots, weakness, iron deficiency
Adolescence	There may be a lot of variability in the early years	Very rare, excessively heavy or prolonged periods

What most often disrupts hormonal regulation of the cycle?

The most common cause of chronic menstrual irregularities during reproductive age is ovulatory dysfunction. This can manifest as infrequent menstruation, absent menstruation, unpredictable delays, or, conversely, irregular, heavy bleeding. When ovulation fails, insufficient progesterone is produced, and the endometrium ceases to undergo its normal secretory phase. [36]

One of the most common causes of this dysfunction is polycystic ovary syndrome. Current guidelines emphasize that even with seemingly regular bleeding, ovulation may be incomplete or absent, and if confirmation of anovulation is needed, serum progesterone levels can be assessed. Polycystic ovary syndrome is characterized by oligomenorrhea, hyperandrogenism, and ovulatory disorders. [37]

Another important mechanism is functional hypothalamic anovulation. It occurs in the context of energy deficiency, weight loss, eating disorders, excessive physical exertion, or severe mental stress. In this case, the central rhythm of gonadotropin-releasing hormone secretion is impaired, and menstrual cycles may become infrequent or disappear altogether. [38]

Hyperprolactinemia, thyroid disease, and premature ovarian failure are also essential. In cases of secondary amenorrhea or severe oligomenorrhea, pregnancy, prolactin, thyroid-stimulating hormone, and ovarian function markers form the basic diagnostic framework. Premature ovarian failure is defined as impaired ovarian function before age 40 and requires a separate approach. [39]

Finally, we must not forget about the structural causes of abnormal uterine bleeding, which go beyond "hormonal imbalance." The PALM-COEIN system identifies polyps, adenomyosis, leiomyomas, hyperplasia, and cancer, as well as coagulopathy, ovulatory dysfunction, endometrial causes, iatrogenic factors, and unclassified conditions. Therefore, irregular or heavy bleeding always requires an assessment of not only hormones but also the uterus as an organ. [40]

Below are the main causes of hormonal imbalances in the cycle. [41]

Cause	How it usually manifests itself	What is particularly alarming
Polycystic ovary syndrome	Infrequent periods, anovulation, signs of hyperandrogenism	Infertility, metabolic disorders
Functional hypothalamic anovulation	Delays or disappearance of menstruation	Weight loss, energy deficiency, stress, excessive loads
Hyperprolactinemia	Oligomenorrhea or amenorrhea	Galactorrhea, headaches, visual disturbances
Thyroid diseases	Irregular cycle, changes in bleeding volume	Symptoms of hypo- or hyperthyroidism
Premature ovarian failure	Infrequent periods, amenorrhea, symptoms of estrogen deficiency	Age up to 40 years
Structural causes according to PALM-COEIN	Heavy, prolonged, intermenstrual bleeding	Anemia, pain, enlarged uterus, age-related risks

When is an examination necessary and which tests are truly informative?

The first rule when a woman's period disappears or is noticeably delayed is to rule out pregnancy. The American Society for Reproductive Medicine explicitly emphasizes that pregnancy should be a primary consideration in the differential diagnosis of secondary amenorrhea. This applies even to cases where the cycle was previously irregular. [42]

If pregnancy is ruled out, further investigation depends on the patient's complaints and clinical presentation. A detailed medical history, assessment of body weight and its changes, physical activity level, diet, psychological stress, presence of acne, hirsutism, galactorrhea, headaches, hot flashes, pelvic pain, and medication effects are often the basis. At this stage, the direction of investigation often becomes clear. [43]

Depending on the situation, laboratory tests most often considered include prolactin, thyroid-stimulating hormone, follicle-stimulating hormone, estradiol, and sometimes progesterone to assess ovulation, as well as tests for hyperandrogenism. If premature ovarian failure is suspected, the focus shifts to ovarian function indicators, and in the case of polycystic ovary syndrome, to signs of chronic anovulation and hyperandrogenism. [44]

A pelvic ultrasound often helps quickly determine the cause. It is particularly useful when polycystic ovarian syndrome, fibroids, polyps, adenomyosis, endometrial hyperplasia, and other structural causes of bleeding are suspected. However, ultrasound does not replace a clinical assessment of ovulation and hormonal status, but rather complements them. [45]

An examination is especially important if periods have been absent for 3 months despite previously regular cycles, if the cycle is less than 38 days or more than 24 days, if bleeding lasts more than 8 days, if it is very heavy, accompanied by anemia, intermenstrual bleeding, severe pain, infertility, or symptoms of an endocrine disorder. In such situations, the assessment should not be formal, but targeted and up-to-date. [46]

Below is a practical algorithm for the initial assessment of cycle disorders. [47]

Situation	The first step	What is usually assessed next?
Delayed or absent periods	Rule out pregnancy	Prolactin, thyroid-stimulating hormone, follicle-stimulating hormone, estradiol, anamnesis
Rare irregular cycles	Assess ovulatory function	Polycystic ovary syndrome, body weight, stress, physical activity
Heavy menstruation	Assess the severity of blood loss and anemia	Structural causes, coagulopathies, PALM-COEIN
Intermenstrual bleeding	Exclude pregnancy and local pathology	Ultrasound, cervix, endometrium, medications
Symptoms of estrogen deficiency before age 40	Consider premature ovarian failure	Repeat hormonal assessment and further management

Conclusion

Hormonal regulation of the menstrual cycle is a complex, multi-level system in which the hypothalamus sets the rhythm, the pituitary gland controls the ovaries, the ovaries shape the estradiol and progesterone profile, and the endometrium mediates the final tissue response. A physiological cycle is impossible without pulsatile secretion of gonadotropin-releasing hormone, normal ovulation, a complete luteal phase, and a proper endometrial response. [48]

For clinical practice, two points are most important. First, there is no single "ideal" number of days that everyone must experience. Second, irregularity, heaviness, duration, or absence of periods should be assessed using modern criteria, rather than automatically attributed to stress or "hormonal imbalance." This approach allows for the timely recognition of polycystic ovary syndrome, functional hypothalamic anovulation, thyroid disease, hyperprolactinemia, premature ovarian failure, and structural causes of abnormal uterine bleeding. [49]