Hypothalamic–pituitary–gonadal axis
This ultrasensitive response is enhanced by the involvement of multiple mitogen-activated protein kinases (MAPKs), including ERK1/2, JNK, p38, and ERK5, which form a complex network of feedback and feedforward loops.
[5] This ultrasensitive mechanism ensures that small changes in GnRH pulse frequency can lead to significant alterations in gonadotropin synthesis, thereby fine-tuning the reproductive endocrine system.
[8] Kisspeptin's influence extends beyond the hypothalamus, as it has been shown to have direct effects on the pituitary and ovaries, regulating processes such as follicle development, oocyte maturation, and ovulation.
At the pituitary level, leptin directly stimulates the release of LH and, to a lesser extent, FSH via nitric oxide synthase activation in gonadotropes.
Ghrelin's action on GnRH neurons involves a decrease in the frequency of GABAergic miniature postsynaptic currents and is dependent on retrograde endocannabinoid signaling.
Insulin sensitivity in GnRH neurons is important for maintaining normal reproductive function, particularly in the face of metabolic challenges such as obesity.
Ghrelin, on the other hand, acts as a signal of energy insufficiency, with persistently elevated levels potentially delaying the normal timing of puberty.
Additionally, the effects of these hormones on GnRH secretion can vary depending on the stage of the estrous cycle, nutritional status, and other physiological factors.
From a larger picture, the HPO axis exhibits a concept known as bistability which is responsible for the maintenance of a cyclical pattern in ovarian activity.
This bistability is most obvious in the transition between the follicular and luteal phases, and arises from interactions between positive and negative feedback loops involving GnRH, LH, FSH, estrogen, and progesterone.
The distinct hormone profiles characterizing each phase represent two stable states, with sharp transitions between them ensuring proper timing of ovulation and endometrial preparation.
These dimeric glycoprotein hormones, primarily produced by granulosa cells in the ovary, act as negative feedback regulators of FSH secretion from the anterior pituitary.
This increase in inhibin B, along with rising estrogen levels, contributes to the suppression of FSH secretion, which is critical for the selection of a single dominant follicle.
The declining steroid production by the corpus luteum and the dramatic fall of inhibin A towards the end of the luteal phase allow for FSH to rise during the last few days of the menstrual cycle.
The corpus luteum's lifespan is influenced by LH pulse frequency and amplitude, gonadotropin levels, and luteotropic factors like prolactin, oxytocin, and prostaglandins.
For instance, in polycystic ovary syndrome (PCOS), alterations in the GnRH pulse generator and abnormal androgen feedback may lead to a persistent high-LH state.
The hyperandrogenism creates a self-perpetuating cycle, in which the increased GnRH pulse frequency promotes LH secretion over FSH, resulting in a high LH/FSH ratio.
[17] Understanding the bistable nature of the HPO axis has significant implications for developing novel therapeutic approaches to restore normal reproductive function.
For example, pulsatile GnRH administration has shown promise in restoring normal reproductive function in certain cases of hypothalamic amenorrhea by nudging the system back into its active state.
Similarly, novel kisspeptin analogs are being developed to modulate the HPO axis more precisely, potentially offering new treatments for infertility and hormone-dependent cancers.
[18] In females, the positive feedback loop between estrogen and luteinizing hormone help to prepare the follicle in the ovary and the uterus for ovulation and implantation.
When the egg is released, the empty follicle sac begins to produce progesterone to inhibit the hypothalamus and the anterior pituitary thus stopping the estrogen-LH positive feedback loop.
During the follicular phase, rising estrogen levels from developing follicles exert positive feedback on the hypothalamus and pituitary, leading to the LH surge that triggers ovulation.
After ovulation, the corpus luteum produces progesterone, which inhibits GnRH secretion from the hypothalamus and gonadotropin release from the anterior pituitary, thus terminating the estrogen-LH positive feedback loop.
[21] Beyond infertility, the diminished level of estrogen causes other effects such as increased bone resorption, unfavorable lipid profiles, hair loss, and skin dryness.
For example, women with eating disorders tend to have oligomenorrhea (prolonged menstrual cycles greater than 35 days) and secondary amenorrhea (absence of menstruation for at least three consecutive months).
Without adequate stimulation from these gonadotropins, ovarian follicles fail to develop properly, leading to insufficient estrogen production and anovulation.
Leptin, an adipocyte-derived hormone discussed under the Regulation section of this Wikipedia page, is significantly reduced in patients with anorexia nervosa due to the loss of body fat.
[32] In bulimia nervosa, while patients may not always present with significant weight loss, the cycle of binge eating and purging can still lead to metabolic disturbances that affect the HPG axis.
Furthermore, the psychological stress associated with bulimia nervosa can activate the HPA axis, leading to elevated cortisol levels that can interfere with normal reproductive function.
