阅读说明：本技术 人绒毛膜促性腺激素在制备早发性卵巢功能不全患者的助孕药物中的应用 (Application of human chorionic gonadotropin in preparation of pregnancy-assisting medicine for patients with premature ovarian insufficiency ) 是由 陈晓 徐键 喻员员 胡瑛瑛 李游江 于 2021-08-05 设计创作，主要内容包括：本发明涉及制药技术领域,特别是涉及人绒毛膜促性腺激素在制备早发性卵巢功能不全患者的助孕药物中的应用。发明利用人绒毛膜促性腺激素制备的药物,通过将患者的FSH降到＜15mIU/ml,LH降到＜10mIU/ml,再一次性给患者肌肉注射HCG 10000U,可通过体内激活休眠卵泡,从而使POI患者获得带有自己遗传基因的后代,且具有经济、方便、无痛苦的优势。(The invention relates to the technical field of pharmacy, in particular to application of human chorionic gonadotropin in preparation of a pregnancy-assisting medicament for patients with early ovarian insufficiency. The invention uses human chorionic gonadotropin to prepare medicine, decreases FSH of patient to less than 15mIU/ml, LH to less than 10mIU/ml, and injects HCG 10000U to patient muscle once again, so that the POI patient can obtain offspring with self genetic gene by activating dormant follicle in vivo, and the invention has the advantages of economy, convenience and no pain.)

1. The application of human chorionic gonadotropin in preparing pregnancy assisting medicine for early ovarian insufficiency patient.

2. A pregnancy promoting pharmaceutical composition for a patient with premature ovarian failure, comprising separately packaged human chorionic gonadotropin.

3. The medicament of claim 2, further comprising an estrogen preparation and a progestin preparation in separate packages.

4. The medicament of claim 3, wherein the estrogen preparation comprises an estradiol valerate preparation;

the progestogen formulation includes a medroxyprogesterone acetate formulation.

5. The medicament of claim 4, wherein said estradiol valerate formulation comprises bulgar.

6. A medicament as claimed in claim 4, wherein said medroxyprogesterone acetate formulation comprises medroxyprogesterone tablets.

Technical Field

The invention relates to the technical field of pharmacy, in particular to application of human chorionic gonadotropin in preparation of a pregnancy-assisting medicament for patients with early ovarian insufficiency.

Background

Early ovarian insufficiency (POI) refers to a clinical syndrome of decline of ovarian activity in women before the age of 40, characterized by menstrual disorders (e.g., amenorrhea or infrequent menstruation) accompanied by high gonadotropins and low estrogens. Characteristics of patients with POI: ovarian follicle depletion lacks growing follicles, leaves few resting follicles (< 1000), and conventional ovulation-promoting drug treatment is ineffective. POI is mainly caused by sex chromosome and autosomal gene defects, autoimmune dysfunction, infection or iatrogenic factors. However, nearly 50% of POI causes are ambiguous. Egg feeding is currently the most effective treatment, but patients do not have access to offspring carrying their own genetic genes.

There are several methods of assisted pregnancy that activate resting follicles in POI patients in vitro, such as: autologous transplantation after In Vitro Activation (IVA) of primordial follicles, injection of platelet-rich plasma (PRP) or stem cells into ovaries, ovarian transplantation, mitochondrial replacement therapy, etc., are expensive and have uncertain therapeutic effects. At present, no research report on in vivo activation of dormant follicles exists at home and abroad.

Disclosure of Invention

In order to solve the problems, the invention provides the application of human chorionic gonadotropin in preparing a pregnancy-assisting medicament for patients with premature ovarian insufficiency. The medicine prepared by using the human chorionic gonadotropin can activate dormant follicles in vivo, so that POI patients can obtain offspring with own genetic genes, and the medicine has the advantages of economy, convenience and no pain.

In order to achieve the above purpose, the invention provides the following technical scheme:

the invention provides an application of human chorionic gonadotropin in preparing a pregnancy-assisting medicament for patients with premature ovarian insufficiency.

The invention also provides a pregnancy-assisting medicament for patients with premature ovarian failure, which comprises human chorionic gonadotropin which is packaged independently.

Preferably, the medicament further comprises an estrogen preparation and a progestin preparation in separate packages.

Preferably, the estrogen preparation comprises an estradiol valerate preparation;

the progestogen formulation includes a medroxyprogesterone acetate formulation.

Preferably, the estradiol valerate formulation comprises bubal.

Preferably, the medroxyprogesterone acetate preparation comprises medroxyprogesterone tablets.

Has the advantages that:

the invention provides an application of human chorionic gonadotropin in preparing a pregnancy-assisting medicament for patients with premature ovarian insufficiency. The invention uses human chorionic gonadotropin to prepare medicine, reduces FSH of a patient to be less than 15mIU/ml and LH to be less than 10mIU/ml by estrogen and/or progestogen, and injects HCG 10000U to the muscle of the patient once again, so that the dormant follicle can be activated in vivo, and the POI patient can obtain offspring with own genetic genes, and the invention has the advantages of economy, convenience and no pain.

Drawings

FIG. 1 is a diagram of the stages in culturing embryos after ova removal in example 2, wherein A is a D1 embryo, B is a D2 embryo, and C is a D3 embryo;

FIG. 2 is a diagram of D5 blastocysts in example 2

FIG. 3 is a picture of a boy infant three days after birth in example 2;

FIG. 4 is a diagram of the stages in culturing the embryos of example 3 after ova retrieval, wherein A is the D1 embryo, B is the D2 embryo, and C is the D3 embryo;

FIG. 5 is a diagram of a D5 sac embryo in example 3;

FIG. 6 is a diagram of intrauterine single fetus survival suggested by B-ultrasound 28 days after transplantation.

Detailed Description

The invention provides an application of human chorionic gonadotropin in preparing a pregnancy-assisting medicament for patients with premature ovarian insufficiency.

The invention also provides a pregnancy-assisting medicament for patients with premature ovarian failure, which comprises human chorionic gonadotropin which is packaged independently.

In the present invention, the medicament preferably further comprises an estrogen preparation and a progestin preparation packaged separately; the estrogen preparation preferably comprises an estradiol valerate preparation; the estradiol valerate formulation preferably comprises buele; the progestogenic formulation preferably includes a medroxyprogesterone acetate formulation; the medroxyprogesterone acetate preparation preferably comprises medroxyprogesterone tablets. The source of the estrogen and progestin is not particularly required for the present invention and commercially available products well known to those skilled in the art may be used.

The invention uses human chorionic gonadotropin to prepare medicine, FSH of a patient is reduced to be less than 15mIU/ml and LH is reduced to be less than 10mIU/ml by estrogen and progestogen, HCG 10000U is injected into the muscle of the patient once again, the recruitment of follicles can be increased after proper HCG is injected, and the improvement of the activity of FSH induced aromatase is promoted, so that the total level of estradiol (E2) in serum is increased, and the recruitment of the number of follicles and the development and maturation of small follicles are further promoted; in addition, the HCG is injected appropriately, so that the HCG is combined with LH receptors (LHR) in granulocytes on the wall layer to quickly induce the expression of Epidermal Growth Factor (EGF), the EGF receptors (EGFR) in granulocytes and cumulus cells are activated through autocrine and paracrine actions, and mitogen-activated protein kinase (MAPK) which is a key factor for promoting cell proliferation and differentiation is further activated, and the granulocytes are stimulated to proliferate, the cumulus is induced to expand and the oocytes are matured; meanwhile, after proper HCG is injected, Luteinizing Hormone (LH) can be increased, high LH increases secretion of ovogenous growth factor GDF-9 and bone morphogenetic protein 15(BMP-15), and further promotes cumulus expansion and oocyte maturation; in addition, the proliferated GDF-9 can also remarkably enhance the in-vitro growth of the follicle before the antrum induced by FSH, and the in-vivo dormant follicle (the dormant follicle from the secondary follicle to the mature follicle stage) is activated through the regulation, so that a POI patient can obtain the offspring with the genetic gene of the POI patient, and the POI patient has the advantages of economy, convenience and no pain.

The invention preferably also provides a pregnancy assisting method for a patient with early ovarian insufficiency, which comprises the following steps:

the FSH and LH of the patient are reduced to < 15mIU/ml and < 10mIU/ml by estrogen and progestogen, and 10000U of human chorionic gonadotropin is administered to the patient once more.

In the present invention, the mode of administration preferably comprises intramuscular injection. The present invention does not require any particular type of injection, and injection methods known to those skilled in the art may be used.

To further illustrate the present invention, the use of hcg provided by the present invention in the preparation of a pregnancy-assisting drug for patients with premature ovarian failure is described in detail below with reference to the examples, which should not be construed as limiting the scope of the present invention.

Example 1

A pregnancy-assisting medicament for patients with early onset ovarian insufficiency, which consists of the following separately packaged preparations: bujiale, Angongprogesterone tablet and human chorionic gonadotropin.

Example 2

Pair, 31 years old, 0-0-0-0, no contraception and no pregnancy for 1 year. The menstruation appears from 23 years old, the menstrual cycle is 40-180 days, and simultaneously symptoms such as hot flashes, insomnia, dyspareunia and the like are accompanied, and the hormone replacement therapy is interrupted all the time to maintain normal menstruation. And (4, 2017, and 20-day hospital endocrine detection): FSH 95.65mIU/ml, E212 pg/ml and LH 29.75 mIU/ml. Pregnancy is started after marriage in 3 months in 2018, Fenmaotong is orally taken every month to maintain menstruation, B ultrasonic monitoring is carried out every week or every two weeks, and the continuous 1-year B ultrasonic indicates that the ovaries are atrophied and have no follicle.

Initial diagnosis in 6 months and 11 days in 2019. B-ultrasonic diagnosis at the day of initial diagnosis: uterus size 38 x 42 x 40mm, muscle layer echo was uniform; left ovary 12 x 7mm, ovary parenchyma, no follicle seen; right ovary 12 x 9mm, ovary parenchyma, no follicle was seen. FSH 32.2mIU/ml, E250pg/ml and LH 21.91 mIU/ml; AMH: less than 0.01 ng/ml; female karyotype 46, XX.

The treatment process comprises the following steps: estrogen + progestin (Bujiale taken twice a day, 2mg each time and 8mg of Angongprogesterone taken once a day) for 3 months, and no follicle was found in both ovaries monitored by B-ultrasound. HCG 10000U were administered once when FSH12.69mIU/ml, E297 pg/ml, LH 6.89mIU/ml in patients, continued to receive the above estrogen + progestin regimen, and monitored the follicles weekly for B-ultrasound. On day 43 after HCG treatment, 18.5mm follicles were found in the left ovary (day hormone: E2261 pg/ml, FSH 4.36mIU/ml, LH 4.44mIU/ml), 1 mature ovum was obtained by immediate injection of triptorelin 0.2mg + HCG 5000U trigger every other day, and 1 excellent embryo (8CI) (C in FIG. 1) was obtained by culturing and cryopreservation. The ova were removed and then subjected to the estrogen plus progestin regimen described above, and observed that no ovarian follicles were found after 44 days. Subsequently, the patient was injected with HCG 10000U 1 time, but no follicle was observed for 7 months. The patients subsequently underwent freeze-thaw embryo transfer assisted pregnancy, and required continued capsule culture after thawing the embryos, and after 2 days of culture, 1 blastocyst was obtained (fig. 2), and were pregnant after transfer. A healthy boy baby (3.65kg) was born by caesarean section at full term of 21 days 4 months in 2021 (the boy baby three days after birth is shown in FIG. 3).

Example 3

Luzhi, 31 years old, 1-0-0-1, no contraception and no pregnancy for 7 years. The patient was born with the birth time of the first day for 7 years, and thereafter, was not pregnant without contraception. The menstrual cycle is advanced at 26 years old, menstrual cycle disorder occurs in nearly 2 years, progesterone is required to be withdrawn and bleed, hot flashes and insomnia begin to appear 1 year ago, and the menstruation is maintained by intermittent administration of fenmatong. Antral follicles were not observed in the continuous 1-year ultrasound B monitoring. bFSH 32.26mIU/ml in 4 months in 2019; 7 months in 2019 bFSH 52.67 mIU/ml; FSH 64.83mIU/ml and AMH 0.01ng/ml at month 4 of 2020.

Initial diagnosis in 5/15/2020. The day of initial diagnosis, type-B ultrasound indicated bilateral ovarian atrophy (Lov 12 x 9; Rov 12 x 10), excessive echo, and no follicles in both ovaries. Chromosome karyotype 46, XX. FSH 36.36mIU/ml, E2105 pg/ml and LH 22.23 mIU/ml.

The treatment process comprises the following steps: estrogen + progestin (Bujiale taken twice a day, 2mg each time and 8mg of Angongprogesterone taken once a day) for 3 months, and no follicle was found in both ovaries monitored by B-ultrasound. When the patient FSH 13.60mIU/ml, E295 pg/ml and LH 7.33mIU/ml, HCG 10000U are administered once, the treatment scheme of the estrogen and the progestogen is continuously received, and the follicle is monitored by B ultrasonic once a week. At 76 days after HCG treatment, 1 follicle of 9.5mm was found in the left ovary (current day hormone: E2107.4 pg/ml, FSH 12.98mIU/ml, LH 6.91mIU/ml), the follicle developed to 13.5mm (current day hormone: E2128.64pg/ml, FSH 9.11mIU/ml, LH 6.19mIU/ml) at intervals of 2 days, the follicle developed to 15.5mm (current day hormone: E2169.58 pg/ml, FSH 8.43mIU/ml, LH 5.98mIU/ml) at intervals of 2 days, the follicle developed to 17.5mm (current day hormone: E2191 g/ml, FSH 7.82mIU/ml, LH 6.27mIU/ml) at next day, the follicle developed to 19.0mm (current day hormone: E2219pg/ml, LH 6.32mIU/ml, FSH 5.79mIU/ml), the follicle developed to 19.0mm (current day, the follicle developed to 13.0 mm) at interval of 2mg of embryo (current day, the follicle was obtained by 1.5000 mg of culture medium-day of HCG and the best-quality pattern was obtained by single-day, and (5) line freezing and storing. The ova were removed and then received the above estrogen + progestin regimen, and no ovarian follicles were observed after 5 months. The patients then underwent freeze-thaw embryo transfer assisted pregnancy, and required continued capsule culture after thawing the embryos, and 13 BB blastocyst was obtained after 2 days of culture (FIG. 5), with blood HCG 220mIU/ml at day 11, HCG 820mIU/ml at day 14, E2437.5pg/ml, P20.82 ng/ml after transfer. 28 days after transplantation, ultrasound B indicated a single viable fetus in the uterus (FIG. 6).

In conclusion, the medicine prepared by using the human chorionic gonadotropin can activate dormant follicles in vivo, so that POI patients can obtain offspring with own genetic genes, and the medicine has the advantages of economy, convenience and no pain.

Although the present invention has been described with reference to the preferred embodiments, it should be understood that various changes and modifications can be made therein by those skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.