The paradigm of norgestimate: a third-generation testosterone-derivative progestin with a peripheral anti-androgenic activity and the lowest risk of venous thromboembolism

Figures & data

Figure 1. A) Molecular structure of norgestimate (NGM) and b) of principal metabolites of NGM: norelgestromin (NGMN) and levonorgestrel (LNG)

Table 1. Pharmacokinetic parameters of norgestimate (NGM) and its metabolite norelgestromin (NGMN)

	NGM	NGMN
Long terminal half-life	45–71 hours	>24 hours
Peak plasma concentration	30 minutes	1.5 hours

Figure 2. A) Relative binding affinities of common used progestins to progesterone receptor (PR). natural progesterone is the reference (1). b) Relative binding affinities of common used progestins to androgen receptor (AR). dihydrotestosterone is the reference (1). the assay measures displacement of ³H R5020 from the PR isolated from the uterus of the rabbit. data from reference [9]

Figure 3. Antagonistic mineralocorticoid activity of norgestimate (NGM) and norelgestromin (NGMN), in comparison to spironolactone. data adjusted from reference [11]

Figure 4. Antiandrogenic activities of norgestimate (NGM) in combination with EE. T: testosterone. DHT: dihydrotestosterone. SHBG: sex hormone-binding globulin. AR: androgen receptor. EE: ethinylestradiol. NGM: norgestimate

Figure 5. Progestins inhibit skin 5α-reductase activity in vitro. The most potent inhibitor in comparison to finasteride was norgestimate, followed by levonorgestrel, dienogest, cyproterone acetate, gestodene, norgestrel, norethisterone and 3-keto-desogestrel. No effect was seen with ethinyl estradiol. Data from reference [21]

Figure 6. Relative binding affinity of different progestins for human sex hormone-binding globulin (SHBG) measured as displacement of ‘H-testosterone. data from reference [24]

Table 2. Risk of developing a blood clot (VTE) in a year according to European medicines agency [44]. 1: further studies are ongoing or planned to collect sufficient data to estimate the risk for these products. CHC: combined hormonal contraceptive

	Risk of developing a blood clot (VTE) in a year
Women not using a combined hormonal pill/patch/ring and are not pregnant	About 2 out of 10,000 women
Women using a CHC containing levonorgestrel, norethisterone or norgestimate	About 5–7 out of 10,000 women
Women using a CHC containing etonogestrel or norelgestromin	About 6–12 out of 10,000 women
Women using a CHC containing drospirenone, gestodene or desogestrel	About 9–12 out of 10,000 women
Women using a CHC containing dienogest	About 8–11 out of 10,000 women
Women using a CHC containing chlormadinone or nomegestrol in combination with estradiol^1	Not yet known

Table 3. Experimental process of ethinylestradiol/norgestimate (EE/NGM) in a monophasic or triphasic formulation in relation to its contraceptive efficacy. X: study without a comparator. PI: Pearl index. GSD: gestodene. NGL: norgestrel, LNG: levonorgestrel

Outcomes	Sample size	Country	Comparator	Design	PI	Reference
Contraceptive efficacy	N = 59,701	Germany	X	Monophasic, non comparative	0.25	Runnebeaum [46]
	N = 97	Austria	X	Monophasic, non comparative	0	Huber [47]
	N = 147	Germany	X	Monophasic, non comparative	0	Becker [48]
	N = 189	Italy	GSD	Monophasic, comparative	0	Affinito [60]
	N = 1473	United States	NGL	Monophasic, comparative	EE/NGM 1.03 EE/NGL 0.86	Corson [50]
	N = 661	France	X	Triphasic, non comparative	0.55	Gauthier [49]
	N = 4234	United States	LNG	Triphasic, comparative	EE/NGM 0.94 EE/LNG 0.80	London [51]

Figure 7. Percentage change from baseline in serum lipids and lipoproteins: all users of monophasic EE/NGM and EE/NG. EE: ethinyl-estradiol. NGM: norgestimate. NGL: norgestrel *: Two-sided t-test significant at the 5% level. modified from reference [50]

Table 4. Experimental process of ethinylestradiol/norgestimate (EE/NGM) in a monophasic or triphasic formulation in relation to its safety and tolerability. X: study without a comparator. GSD: gestodene. NGL: norgestrel, LNG: levonorgestrel

Outcomes	Sample size	Country	Comparator	Design	Withdrawal rates for weight gain	Reference
Safety and tolerability	N = 59,701	Germany	X	Monophasic, non comparative	/	Runnebeaum [46]
	N = 97	Austria	X	Monophasic, non comparative	1%	Huber [47]
	N = 147	Germany	X	Monophasic, non comparative	0	Becker [48]
	N = 1473	United States	NGL	Monophasic, comparative	EE/NGM 1% EE/NGL 1.4%	Corson [50]
	N = 140	Thailand	LNG	Monophasic, comparative	0	Tantbirojn [59]
	N = 189	Italy	GSD	Monophasic, comparative	/	Affinito [60]
	N = 1783	United States	X	Triphasic, non comparative	/	Andolsek [58]
	N = 661	France	X	Triphasic, non comparative	0.16%	Gauthier [49]
	N = 66		LNG	Triphasic, comparative	0	Janaud [61]

Table 5. Experimental process of ethinylestradiol/norgestimate (EE/NGM) in a monophasic or triphasic formulation in relation to its bleeding pattern. X: study without a comparator. %*: percentage of cycles. %+: percentage of patients. BTB: breakthrough bleeding. GSD: gestodene. NGL: norgestrel, LNG: levonorgestrel, DSG: desogestrel

Outcomes	Sample size	Country	Comparator	Design	Normal cycles at the of treatment	BTB at the end of treatment	Reference
Bleeding pattern	N = 59,701	Germany	X	Monophasic, non comparative	98.6%	3%^+	Runnebeaum [46]
	N = 1473	United States	NGL	Monophasic, comparative	EE/NGM 99.6% EE/NGL 98.6%	EE/NGM 5.1%* EE/NGL 6.3%*	Corson [50]
	N = 140	Thailand	LNG	Monophasic, comparative	/	EE/NGM 0^+ EE/LNG 1.5%^+	Tantbirojn [59]
	N = 189	Italy	GSD	Monophasic, comparative	EE/NGM 96.3% EE/GTD 96.7%	EE/NGM 1.6%* EE/GTD 0.2%*	Affinito [60]
	N = 1783	United States	X	Triphasic, non comparative	0	2.4%*	Andolsek [58]
	N = 661	France	X	Triphasic, non comparative	96.3%	2.6%^+	Gauthier [49]
	N = 201	Thailand	DSG	Multiphasic, comparative	/	EE/NGM 10.8%^+ EE/DSG 7.4%^+	Jaisamrarn [65]

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