HMG

What is the research background of HMG?

The Development of Early Reproductive Endocrine Theory

At the end of the 19th century and the beginning of the 20th century, scientists gradually recognized the crucial role of the endocrine system in regulating human physiological functions. With the in-depth study of reproductive physiology, people began to understand that the gonadotropins secreted by the pituitary gland play a key regulatory role in the development of the gonads and reproductive functions. This laid the theoretical foundation for the subsequent discovery and research of HMG.

The Discovery of HMG

In the 1930s, researchers found that the urine of postmenopausal women contained a substance that could promote the development of the gonads. At that time, through bioassays, it was observed that injecting the urine of postmenopausal women into experimental animals could cause changes in the animals' gonads. This discovery initiated the research on the gonadotropin substances in the urine of postmenopausal women.

After years of research and the development of purification techniques, it was not until the 1950s that scientists successfully isolated the substance with gonadotropin activity from the urine of postmenopausal women and named it Human Menopausal Gonadotropin (HMG).

The Source of HMG

HMG is mainly derived from the urine of postmenopausal women. After menopause, the ovarian function of women declines, and the secretion of estrogen decreases. The negative feedback effect on the hypothalamus-pituitary axis weakens, leading to an increase in the secretion of gonadotropins by the pituitary gland, including Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone (LH). These hormones are excreted into the urine through the kidneys. Therefore, HMG can be extracted and purified from the urine of postmenopausal women.

The In-depth Research Driven by Clinical Needs

With the deepening of the understanding of HMG, its clinical application value has gradually emerged. At that time, there were many reproductive disorders caused by hypogonadism in clinical practice, such as female ovulation disorders and male hypogonadotropic hypogonadism. The emergence of HMG provided a new treatment method for these diseases.

What is the mechanism of action of HMG?

Stimulating Follicular Development:

Promoting Follicular Growth: 

HMG contains Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone (LH) components. FSH plays a crucial role in the early stage of follicular development. It can stimulate the primordial follicles in the ovary to develop into primary follicles, and further develop into secondary follicles and mature follicles. By binding to the receptors on the granulosa cells of the follicles, FSH activates the intracellular signaling pathway, promotes cell proliferation and differentiation, and increases the synthesis of estrogen in the follicles. The secretion of estrogen, in turn, promotes the expression of FSH receptors, forming a positive feedback mechanism that further promotes the growth and development of the follicles ^[1].

Regulating the Balance of Follicular Growth: 

LH plays an important role in the later stage of follicular development. It binds to the receptors on the theca cells of the follicles and stimulates the synthesis of androgens. Androgens are converted into estrogen in the granulosa cells, further promoting the growth and maturation of the follicles. The LH component in HMG can regulate the ratio of FSH and LH, maintain the balance of follicular growth, and avoid excessive or insufficient stimulation ^[1].

Inducing Ovulation:

Triggering the Ovulation Process: 

When the follicles are mature, the LH component in HMG can trigger the ovulation process. The peak of LH will cause the rupture of the follicular wall and the release of mature eggs. At the same time, LH can also promote the formation of the corpus luteum, which secretes progesterone, providing a suitable environment for the implantation of the fertilized egg and the early development of the embryo^[1].

Regulating the Endocrine System:

Influencing Hormone Levels: 

HMG affects the hormone levels in women's bodies by regulating ovarian function. It can increase the secretion of estrogen, progesterone, and androgens, and these hormones play important regulatory roles in women's reproductive systems, bones, cardiovascular systems, etc. For example, estrogen can maintain the function of women's reproductive organs, promote the growth and repair of the endometrium, and prevent osteoporosis; progesterone can maintain pregnancy and regulate the menstrual cycle, etc.^[1].

Feedback Regulation Mechanism: 

The regulation of the endocrine system by HMG also involves a feedback regulation mechanism. When the hormone levels in the body increase, the hypothalamus and pituitary gland will be inhibited from secreting Gonadotropin-Releasing Hormone (GnRH), FSH, and LH through a negative feedback mechanism, thus regulating the hormone secretion levels and maintaining the balance of the endocrine system^[1].

What are the applications of HMG?

1. Female Infertility Related to Idiopathic Hypogonadotropic Hypogonadism (IHH)

HMG can be used to treat female infertility caused by IHH. By providing FSH and LH, HMG can induce follicular development and ovulation, thus helping patients achieve natural pregnancy or pregnancy through assisted reproductive technologies. For patients who do not respond well to the conventional dose of HMG, the use of a high dose of HMG or combination with other drugs (such as letrozole) can be considered to improve the follicular response^[2].

2. Treatment of Diminished Ovarian Reserve (DOR)

For women with diminished ovarian reserve, HMG can stimulate follicular development by providing a higher concentration of FSH, thus increasing the chance of pregnancy.

3. Prevention and Management of Ovarian Hyperstimulation Syndrome (OHSS)

In assisted reproductive technologies, the use of HMG needs to be cautious to avoid the occurrence of Ovarian Hyperstimulation Syndrome (OHSS). By adjusting the dose and monitoring follicular development, the risk of OHSS can be effectively reduced.

4. Treatment of Male Infertility

HMG contains Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone (LH). The role of FSH it provides can stimulate the growth and development of the seminiferous tubules in the testis and promote spermatogenesis. FSH acts on the Sertoli cells in the testis, promoting the Sertoli cells to secrete androgen-binding protein, increasing the concentration of androgens in the testis, and providing a suitable environment for spermatogenesis. Human Chorionic Gonadotropin (HCG) mimics the role of LH and stimulates the Leydig cells in the testis to secrete testosterone. Testosterone is one of the most important sex hormones in men and plays a vital role in maintaining male secondary sexual characteristics and spermatogenic function. A high concentration of testosterone can promote the maturation and release of sperm. The combined use of HMG and Human Chorionic Gonadotropin (HCG) can mimic the natural effects of FSH and LH in the body and synergistically promote spermatogenesis. This combined treatment method can increase the sex hormone levels in the testis, improve the spermatogenic environment, and increase the quantity and quality of sperm.

5. Applications in Assisted Reproductive Technologies

Promoting Superovulation: 

Some studies have shown that in the superovulation protocol for sheep, injecting HMG once a day and injecting Follicle-Stimulating Hormone (FSH) twice a day for four days can produce comparable superovulation responses and embryo transfer results^[1]. This means that HMG can replace FSH and reduce the number of injections, providing a feasible option for the superovulation protocol of animals.

In human assisted reproductive technologies, HMG is also widely used to promote ovarian ovulation. By stimulating the development of follicles in the ovary, it increases the number of mature eggs and improves the chance of pregnancy.

Inducing Estrus:

 In Awassi ewes, using HMG for estrus induction shows a higher estrus rate and pregnancy rate compared with Pregnant Mare Serum Gonadotropin (PMSG) ^[3]. Specifically, the estrus response percentage in the HMG treatment group is 85% (17/20), and the pregnancy rate is 85% (17/20). This indicates that HMG has a high success rate in the estrus synchronization program for sheep.

HMG is a key gonadotropin widely used in the treatment of male infertility, specific types of female infertility, and assisted reproductive technologies. Its core function lies in supplementing exogenous Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone (LH) to rebuild the hormonal balance in the body, thereby promoting follicular development, ovulation, and spermatogenesis. This mechanism helps regulate the functions of the reproductive system by mimicking the natural hormonal environment of the human body, especially playing an important role in assisted reproductive technologies.

Relevant Citations

[1] Zhang J, Lu X, Liu Y, et al. Potential role for human menopausal gonadotropin in ovine superovulatory regimens  during the breeding season[J]. Reproduction in Domestic Animals, 2023,58(6):726-733.DOI:10.1111/rda.14342.

[2] Ma Y, Li M, Song J, et al. Application of Human Menopausal Gonadotropins in the Treatment of Idiopathic  Hypogonadotropic Hypogonadism (IHH)-Based Infertility in Females: A Case Report[J]. International Medical Case Reports Journal, 2023,16:699-704.DOI:10.2147/IMCRJ.S428018.

[3] Hussein E K, Naoman U T, Al-Ajeli R R. Induction of estrus using human menopausal gonadotrophin in Iraqi Awassi ewes[J]. Iraqi Journal of Veterinary Sciences, 2021:0-0. DOI:10.33899/IJVS.2020.127132.1466