Effect of growth hormone on ovarian function
[Abstract] Growth hormone affects ovarian function by directly binding to the growth hormone receptor on the ovary or by the action of insulin-like growth factor. Basic research indicates that auxin can affect the growth of antral follicles and antral follicles, inhibit follicular atresia, promote follicular maturation, increase the number of ovulation, and may affect the production of sex hormones. Based on the above reasons, many scholars have explored the application value of growth hormone in human assisted ovulation induction therapy. It is expected that auxin can improve the effect of ovulation induction therapy, but the current results are controversial. Improving the use of growth hormone may improve outcomes.
[Key words] growth hormone; ovary; follicle; sex hormone; ovulation
Growth hormone is a hormone secreted by the pituitary gland and has a physiological effect of promoting growth and affecting metabolism. With the in-depth study of reproductive physiology, it is found that growth hormone can
Act on the ovary, affecting ovarian function, such as: stimulate follicular growth, increase the number of ovulation and the production of sex hormones. Effect of growth hormone on ovarian function
1 growth hormone affects ovarian function
It is currently believed that growth hormone affects ovarian function mainly through two ways: 1 Directly combined with growth hormone receptors (GHR) on the ovary to produce biological effects. Studies have found that growth hormone receptors are present in the ovaries of many species, indicating that growth hormone can act directly on the ovaries. Lebedeva et al  found high-affinity growth hormone receptors in follicular granulosa cells and follicular cells before ovulation in chickens. Zhao [ 2 ] used reverse transcription 2 PCR (RT2PCR) to detect the presence of growth hormone receptor mRNA on the anterior antral follicle wall, oocyte and cumulus in the mouse ovary. M archal et al  confirmed that the expression of gh rm rmone (GH) receptor m RNA was observed in cumulus cells and oocytes of pigs and cattle, and growth was observed during oocyte maturation. Hormones can promote oocyte maturation, suggesting that there are functional GH receptors in cumulus cells and oocytes of these two animals; 2 growth hormone indirectly affects ovarian function through insulin-like growth factor (IGF) system . Growth hormone induces IGF production in the liver, including IGF2I and IGF2II. IGF reaches the ovaries through the blood circulation and binds to target cell receptors. In addition, growth hormone can directly induce follicular granulosa cells and follicular cells to produce IGF, which regulates ovarian function through paracrine and autocrine effects. Experiments have confirmed the expression of IGF mRNA in follicles at various stages of sheep ovary .
IGF can act directly on the ovary, and its role is synergistic with the regulation of growth hormone .
2The effect of growth hormone on follicular growth
Follicles are the basic functional unit of the ovaries. Follicles not only undergo morphological changes during development, but also have functional development. Gonadotropins and gonadal hormones play a leading role in this process. However, in the absence of follicle stimulating hormone (FSH), the follicles of FSH knockout mice can still develop into the preantral follicle stage, suggesting that there are other factors affecting follicular development, especially in the early stage of follicular development, FSH may not directly effect. Recent studies have shown that growth hormone affects the growth and development of follicles.
- 1 stimulate the growth of anterior follicles
Growth hormone stimulates antral follicle growth and increases the number of small follicles. Ovarian histology of auxin receptor knockout mice (GHR 2KO) found that the number of anterior antral follicles and antral follicles in the ovary was significantly less than that of wild mice due to the lack of auxin. Treatment with IGF2I not only increases the number of primordial follicles but also reduces follicular follicles . The growth hormone receptor knockout mouse model confirmed that the pre-ovulatory part of follicles (PF) decreased in GHR 2KO mice (42. 9 3. 7 vs 28. 83. 5, P < 0.05), presumably due to lack of growth. Hormone action, leading to a decrease in the number of early follicles.
- 2 effects on antral follicles
Growth hormone enhances the response of antral follicles to gonadotropins. In animal studies, it was found that recombinant bovine growth hormone enhances the response of antral follicles to gonadotropins and shortens the time to recruit dominant follicles . Studies in humans have also suggested that growth hormone has a similar effect. Six patients with growth hormone deficiency received gonadotropin (HM G) + GH ovulation therapy, and found that the FSH threshold level that stimulates follicular development was reduced (ie, the amount of HM G was reduced), and single follicular growth was obtained, suggesting growth hormone It seems that the sensitivity of dominant follicles to FSH can be selectively increased. It has been reported that a patient with primary acromegaly who has undergone controlled ovarian hyperstimulation has successfully delivered triplets, suggesting that high growth hormone levels can enhance the sensitivity of the ovaries to FSH . Although these limited data suggest that growth hormone enhances gonococcal follicle response to gonadotropins, good animal models are needed to conduct basic research to provide sufficient evidence to validate and elucidate specific mechanisms of action.
- 3 promote oocyte maturation
Growth hormone promotes oocyte maturation. Experiments in vitro culture of horse cumulus complex (COC) showed that horse growth hormone promoted oocyte maturation, with 29% of cumulus increasing in the growth hormone group and increasing the percentage of oocytes, while 13% of the control group was enlarged. In the cumulus, horse growth hormone not only increased the number of oocytes in dividing metaphase II, but also increased the maturation rate of oocytes (89% vs 78%, P < 0.05) . Growth hormone-assisted superovulation therapy also supports the results of animal experiments. Growth hormone-assisted treatment significantly increased the number of small follicles (V and V I), the rate of maturation of GV oocytes and the rate of fertilization . Kiapekou  co-cultured with GH and/or IGF2I during immature oocyte culture, and both drugs promoted follicular maturation.
- 4 inhibition of follicular atresia
Animal experiments suggest that growth hormone inhibits follicular atresia. Detection of growth hormone receptor/growth hormone binding protein knockout (GHR/GHBP2KO) in mice and wild mice ovary, the results showed that the former ovary weight loss, tissue structure is good. Despite the presence of follicles at various stages of development, the number of growing follicles is reduced. Further analysis of the ovarian tissue sections showed that the ratio of the atresia follicle/healthy follicle in the ovary of GHR/GHBP2KO mice was significantly higher than that of the latter. The study of follicular apoptosis in transgenic mice overexpressing bovine growth hormone more directly confirms the role of growth hormone in inhibiting follicular atresia. In the ovary of normal mice, 46% of follicles showed apoptosis, while only 30% of transgenic mice showed a significant decrease in follicular apoptosis rate, thereby reducing follicular atresia. These atresia follicles contain a large number of apoptotic cells, mainly apoptotic granulosa cells. Apoptosis is involved in follicles at all levels, but the degree of apoptosis varies at different stages. No obvious apoptosis was observed in follicles before ovulation in transgenic mice or normal mice, but the phenomenon of follicular atresia in early sinus was obvious. The results of this experiment are consistent with the rule of follicular degeneration in most early sinus stages, and also indicate growth hormone. Follicular apoptosis in the early sinus can not be completely inhibited.
3 increase the number of ovulation
Growth hormone not only stimulates follicular growth, but also increases the number of ovulation. Anne et al. studied GHR/GHBP2KO mice and found that the number of ovulation in GHR/GHBP2KO mice was reduced, which in turn caused the number of litters in GHR/GHB P2KO mice to be significantly lower than that in wild mice. In order to clarify the cause, exogenous gonadotropin was used to induce ovulation treatment. The result was an average of 11. 8 2. 3 mice per mouse, while the latter ovulated with an average of 35. 3 2. 3 mice/rat, suggesting GHR / GHBP2KO rats. The ovaries are defective. Ovarian histological analysis of GHR/GHBP2KO rats also confirmed that the number of healthy follicles at various developmental stages in these ovaries was significantly reduced, especially the number of follicles with a diameter of 200 μm was statistically different from that of the control group. The reduction of follicles and the lack of follicles in the terminal stage of GHR/GHBP2KO mouse follicles are responsible for the decrease in the number of ovulations. Studies on follicular apoptosis in transgenic mice have also confirmed that growth hormone can reduce the atresia of follicles at various developmental stages, thereby increasing the likelihood of ovulation.
4 affect the production of estrogen and progesterone
Whether the growth hormone affects the secretion of sex hormones is still controversial.
The growth hormone-containing culture medium cultured granulosa cells and inner follicular cells of porcine follicles in vitro, and the results showed that growth hormone can promote the secretion of estrogen and progesterone; however, when the two cells are co-cultured, whether or not the culture solution is added or not Growth hormone, progesterone production decreased; and the growth hormone secretion decreased more significantly after the addition of growth hormone; but estradiol secretion increased. It was also found that growth hormone enhances the activity of 3β2 hydroxysteroid dehydrogenase (3β2HSD) /Δ5 isomerase. Therefore, growth hormone directly affects the secretion of sex hormones in porcine follicle cells. However, other studies do not support the conclusion that growth hormone affects the activity of related enzymes. In the GHR 2KO mouse model, a decrease in estradiol secretion was observed, but the expression of aromatase and 3β2HSD mRNA was not different from that in normal mice . Another study showed that growth hormone did not affect the expression of P450c17 mRNA and P450 aromatase mRNA in bovine ovary, and therefore did not affect the secretion of sex hormones. Whether the growth hormone affects the ovarian secretion of steroid hormones needs further research.
5 application of growth hormone in promoting ovulation
In view of a large number of experiments, nutropin aq growth hormone can stimulate the growth of follicles, the production of ovarian steroid hormones, and enhance the responsiveness of ovaries to FSH. More and more scholars have applied it to the adjuvant treatment of ovulation.
In animal ovulation induction therapy, growth hormone has a clear auxiliary ovulation induction effect. Gonzalez et al  used GH / gonadotropin-releasing hormone agonist (GnRHa) + FSH, FSH and 7 drugs to induce ovulation without any drug, the number of oocytes was 8. 7 0. 9, 6. 8 1. 3 and 4. 5 0. 8 (P < 0.05), the results confirmed that growth hormone increased the number of follicles that responded to FSH, thereby increasing the rate of ovulation. Starbuck et al  used recombinant GH combined with artificial insemination to treat cows, and the pregnancy rate was significantly improved (60.3% vs 40.3%, P < 0.05). The pregnancy rate of cows with milk production for more than 100 days increased. Significant (64.3% vs 25.8%). GH has a good auxiliary ovulation effect, which makes it have high application value in the livestock industry.
In human assisted reproductive therapy, many scholars have also conducted corresponding research. Wang Ying et al  reported the use of growth hormone-assisted ovulation therapy in 7 patients with polycystic ovary syndrome (PCO S). The results showed that growth hormone adjuvant therapy reduced HM G dosage, shortened HM G stimulation time, and increased the advantage. The number of follicles. It has been confirmed that growth hormone adjuvant therapy can increase the rate of ovulation. Tesarik et al used GH to assist ovulation treatment in infertile women over 40 years old. The results showed that the number of follicles in the two groups was similar, but the abortion rate of auxin group was lower than that of the control group, and the peak of estrogen, delivery rate and live birth rate were higher than that of the control. group. The results may be related to growth hormone improving follicular developmental potential. From these results, GH has a certain effect in assisting ovulation induction therapy.
However, other studies have not shown optimistic results. In a large, multicenter, randomized, double-blind study, 96 infertile ovarian-responsive infertile patients received growth hormone-releasing factor-assisted ovulation therapy, and the results showed that growth hormone releasing factor induced a significant increase in endogenous growth hormone. However, the pregnancy rate and abortion rate were similar in the control group (100 patients) who received placebo adjuvant therapy. The pregnancy rates were 8.3% and 8%, respectively, and the abortion rate was 12.5%, 16 %. The results of a meta-analysis of previous growth hormone ovulation therapy by Tarlatzis  showed that the efficacy of growth hormone ovulation in the treatment of patients with low ovarian response was not obvious.
From the above data, the efficacy of growth hormone to promote ovulation is still controversial. In summary, the results of animal experiments confirmed the presence of growth hormone receptors on the ovary, growth hormone involved in the regulation of ovarian function, but its specific regulation mechanism is not very clear, especially the mechanism of action on antral follicles. Although transgenic animal models provide information on the effects of growth hormone on morphological changes in the ovary, how these changes are induced requires further investigation. Due to species differences, the conclusions of animal experiments cannot be directly applied to humans; there is still a lack of basic research on the relationship between human growth hormone and ovarian function; in clinical applications, the application value of growth hormone in assisting superovulation therapy is still controversial, but Two distinct conclusions may be related to the selection of different subjects and different experimental methods. According to the results of animal experiments, growth hormone mainly affects the early stage of follicular development–the pre-anterior follicular stage. However, in ovulation induction therapy, growth hormone is generally used in synchrony with gonadotropin in the early follicular phase. Therefore, it is only It acts on the antral follicle stage and is not enough to affect the antral follicles. If you change the timing of the use of growth hormone, prolonging the use of time may improve the efficacy of its ovulation induction therapy. But a large number of random double-blind studies are needed to confirm this idea. In addition, the doses of growth hormone-assisted ovulation therapy provided by the data need to be different. The appropriate therapeutic dose needs to be further explored, and whether the growth hormone-assisted reproductive offspring has adverse effects still needs long-term follow-up evaluation.