Amenorrhea medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

Overview

Pharmacologic medical therapy is recommended in patients of amenorrhea associated with hypothalamic causes, pituitary causes, ovarian insufficiency, and chronic anovulation. Hormone replacement therapy such as estrogen and progesterone are the mainstay of treatment in patients of amenorrhea.

Medical Therapy

Pharmacologic medical therapy is recommended among patients with hypothalamic causes, pituitary causes, ovarian insufficiency, and chronic anovulation.

Amenorrhea

1 Hypothalamic causes
- 1.1 Adult
  - Preferred regimen (1): Alora 0.05, 0.075, and 0.1 mg transdermal daily, applied twice weekly PLUS medroxyprogesterone acetate 10 mg PO for 12 days each month
  - Preferred regimen (2): Climara 0.025, 0.05, 0.075, and 0.1 mg transdermal daily, applied once weekly PLUS medroxyprogesterone acetate 10 mg PO for 12 days each month
  - Preferred regimen (3): Esclim 0.025, 0.0375, 0.05, 0.075, 0.1 mg transdermal daily, applied twice weekly PLUS medroxyprogesterone acetate 10 mg PO for 12 days each month
  - Preferred regimen (4): Vivelle-dot 0.037, 0.05, 0.075, 0.1 mg transdermal daily, applied twice weekly PLUS medroxyprogesterone acetate 10 mg PO for 12 days each month
  - Preferred regimen (5): Premarin 0.625-1.25 mg PO daily PLUS medroxyprogesterone acetate 10 mg PO for 12 days each month
2 Pituitary causes
- 2.1 Hyperprolactinemia
  - 2.1.1 Drug-induced hyperprolactinemia
    - Preferred regimen (1): Micronized 17-β estradiol 1-2 mg PO daily PLUS medroxyprogesterone acetate 2.5-5.0 mg PO daily (continuous)
    - Preferred regimen (2): Micronized 17-β estradiol 1-2 mg PO daily PLUS medroxyprogesterone acetate 10 mg PO for 12 days each month (sequential)
    - Preferred regimen (3): 17-β estradiol 1-2 mg transdermal daily PLUS micronized progesterone 100 mg PO daily (continuous)
    - Preferred regimen (4): 17-β estradiol 1-2 mg transdermal daily PLUS micronized progesterone 200 mg PO for 12 days each month (sequential)
    - Alternative regimen (1): Cabergoline 0.25 mg PO twice weekly
  - 2.1.2 Prolactinoma
    - Preferred regimen (1): Cabergoline 0.25 mg PO twice weekly (can increase to 0.25 mg four times a week up to 1 mg twice weekly)
    - Preferred regimen (2): Bromocriptine 1.25-2.5 mg PO daily initially (may increase by 2.5 mg/day every 2-7 days). Up to 30 mg PO daily
    - Preferred regimen (3): Alora 0.05, 0.075, and 0.1 mg transdermal daily, applied twice weekly PLUS medroxyprogesterone acetate 10 mg PO for 12 days each month
    - Preferred regimen (4): Climara 0.025, 0.05, 0.075, and 0.1 mg transdermal daily, applied once weekly PLUS medroxyprogesterone acetate 10 mg PO for 12 days each month
    - Preferred regimen (5): Esclim 0.025, 0.0375, 0.05, 0.075, 0.1 mg transdermal daily, applied twice weekly PLUS medroxyprogesterone acetate 10 mg PO for 12 days each month
    - Preferred regimen (6): Vivelle-dot 0.037, 0.05, 0.075, 0.1 mg transdermal daily, applied twice weekly PLUS medroxyprogesterone acetate 10 mg PO for 12 days each month
    - Preferred regimen (7): Premarin 0.625-1.25 mg PO daily PLUS medroxyprogesterone acetate 10 mg PO for 12 days each month
  - 2.1.3 Resistant and malignant prolactinoma
    - Preferred regimen (1): Cabergoline 1 mg PO twice weekly
    - Preferred regimen (2): Bromocriptine 30 mg PO daily
    - Preferred regimen (3): Temozolomide 150–200 mg/m² IV infusion for five of every 28 days^[1]
  - 2.1.4 Prolactinoma during pregnancy
    - Preferred regimen (1): Bromocriptine 1.25-2.5 mg PO daily initially (may increase by 2.5 mg/day every 2-7 days). Up to 30 mg PO daily
3 Ovary insufficiency
- 3.1 Premature ovarian insufficiency^[2]
  - 3.1.1 Adult
    - Preferred regimen (1): Micronized 17-β estradiol 1-2 mg PO daily PLUS medroxyprogesterone acetate 2.5-5.0 mg PO daily (continuous)
    - Preferred regimen (2): Micronized 17-β estradiol 1-2 mg PO daily PLUS medroxyprogesterone acetate 10 mg PO for 12 days each month (sequential)
    - Preferred regimen (3): 17-β estradiol 1-2 mg transdermal daily PLUS micronized progesterone 100 mg PO daily (continuous)
    - Preferred regimen (4): 17-β estradiol 1-2 mg transdermal daily PLUS micronized progesterone 200 mg PO for 12 days each month (sequential)
    - Alternative regimen (1): Conjugated equine estrogen 0.625-1.25 mg PO daily PLUS micronized progesterone 100 mg PO daily (continuous)
    - Alternative regimen (2): Conjugated equine estrogen 0.625-1.25 mg PO daily PLUS micronized progesterone 200 mg PO for 12 days each month (sequential)
- 3.2 Turner syndrome^[3]
  - 3.2.1 12-13 years old
    - Preferred regimen (1): Depot 17-β estradiol 0.2–0.4 mg IM every month
    - Alternative regimen (1): 17-β estradiol 6.25 μg transdermal daily
    - Alternative regimen (2): Micronized 17-β estradiol 0.25 mg PO daily
  - 3.2.2 12.5-15 years old
    - Gradually increase 17-β estradiol dose over about 2 years (e.g., 14, 25, 37, 50, 75, 100, 200 μg daily via patch) to adult dose, as following:
      - Preferred regimen (1): 17-β estradiol 100–200 μg transdermal daily
      - Preferred regimen (2): Micronized estradiol 2–4 mg PO daily
      - Preferred regimen (3): Ethinyl estradiol 20 μg PO daily
      - Preferred regimen (4): Conjugated equine estrogen 1.25–2.5 mg PO daily
  - 3.2.3 14-16 years old
    - Preferred regimen (1): Micronized progesterone 200 mg PO daily on the 20th–30th days of monthly cycle
    - Preferred regimen (2): Micronized progesterone 200 mg PO daily on the 100th–120th days of 3-month cycle

4 Chronic anovulation
- 4.1 Polycystic ovary syndrome (PCOS)
  - 4.1.1 Adult
    - Preferred regimen (1): Clomiphene citrate 50 mg PO daily for 5 days (starting on day 2–5 following a spontaneous or progestin-induced withdrawal bleeding)^[4]
    - Preferred regimen (2): Metformin 500 mg PO q8h (lactic acidosis in renal impairment)^[5]
    - Preferred regimen (3): Follicle stimulating hormone (FSH) 37.5–75 IU SC or IM daily^[6]
    - Alternative regimen (1): Tamoxifen 20 to 80 mg PO daily during the cycle^[7]
    - Alternative regimen (2): Sibutramine 10 mg PO daily^[8]
    - Alternative regimen (3): Orlistat 120 mg PO q8h^[9]
    - Alternative regimen (4): Troglitazone 300-600 mg PO daily (weight gain)^[10]
    - Alternative regimen (5): Follicle stimulating hormone (FSH) 150 IU SC or IM daily [cause ovarian hyperstimulation syndrome (OHSS)]^[11]
  - 4.1.2 Pediatric
    - Preferred regimen (1): Metformin 1.50–2.55 g PO per day^[12]

Oral contraceptive pills (OCPs)

Different studies have shown that OCP therapy can slow down the bone loss process in patients with exercise- and anorexia-associated amenorrhea. The detailed results are as following table:^[13]

Type of amenorrhea	Medicine		Dosage	Treatment duration	Bone mineral density (BMD) site	Outcome
Exercise-associated functional amenorrhea	Ethinyl estradiol		0.035 mg	12 months	Lumbar spine and femoral neck	Increased BMD in all sites^[14]
	Norethindrone Medroxyprogesterone		0.5-1.0 mg 10 mg	12 months	Lumbar spine and femoral neck	Increased BMD in all sites^[14]
	Ethinyl estradiol		0.03 or 0.02 mg	12 months	Lumbar spine	Increased BMD in all sites^[15]
	Desogestrel		0.15 mg	12 months	Lumbar spine	Increased BMD in all sites^[15]
	Ethinyl estradiol		0.030 mg	10 months	Lumbar spine and legs	Increase BMD in lumbar spine not in legs^[16]
	Levonorgestrel		0.150 mg	10 months	Lumbar spine and legs	Increase BMD in lumbar spine not in legs^[16]
	Ethinyl estradiol		0.05 mg	8 months	Lumbar spine and radius	Increase BMD in lumbar spine not in radius^[17]
	Cyproterone acetate		2 mg	8 months	Lumbar spine and radius	Increase BMD in lumbar spine not in radius^[17]
	Conjugated estrogen		0.0625 mg	24 months	Lumbar spine and femoral neck	Increased BMD in all sites^[18]
	Transdermal estradiol		0.05 mg	24 months	Lumbar spine and femoral neck	Increased BMD in all sites^[18]
	12 days	Estriol	1 mg	9.3 months	Lumbar spine, femoral neck, and trochanter	No change BMD in any sites^[19]
	12 days	Estradiol	2 mg
	10 days	Estriol	1 mg
		Estradiol	2 mg
		Norethisterone	1 mg
	6 days	Estriol	0.5 mg
	6 days	Estradiol	1 mg
	Premarin		0.625 mg	24 months	Lumbar spine, wrist, and foot	Increase BMD in lumbar spine, neither in wrist nor in foot^[20]
	Provera		10 mg	24 months	Lumbar spine, wrist, and foot
	Ethinyl estradiol		0.035 mg	10 months	Lumbar spine and femoral neck	Increase BMD in lumbar spine not in femoral neck^[21]
	Norgestimate		0.180–0.250 mg	10 months	Lumbar spine and femoral neck	Increase BMD in lumbar spine not in femoral neck^[21]
Anorexia-associated functional amenorrhea	Ethinyl estradiol		0.020–0.035 mg	12 months	Lumbar spine and femoral neck	No change BMD in any sites^[22]
	Norgestimate Norgestrel Norethindrone acetate Levonorgestrel		0.180–0.250 mg 0.5 mg 0.5-1.0 mg -	12 months	Lumbar spine and femoral neck	No change BMD in any sites^[22]
	Ethinyl estradiol		0.05 mg	12 months	Lumbar spine	No change BMD^[23]
	Norgestrel		0.5 mg	12 months	Lumbar spine	No change BMD^[23]
	Premarin		0.625 mg	18 months	Lumbar spine	No change BMD^[24]
	Provera		5 mg
	Ethinyl estradiol		0.035 mg
	Premarin		0.3–0.625 mg daily	4.3 years	Lumbar spine and femoral neck	Increased BMD in all sites^[25]
	Ethinyl estradiol		0.020 mg	12 months	Lumbar spine and femoral neck	No change BMD in any sites^[26]
	Levonorgestrel		0.1 mg
	Dihydroepiandrostendion (DHEA)		50 mg daily
	Recombinant IGF-1		30 mg/kg twice daily	9 months	Lumbar spine, femoral neck, and radius	No change BMD in any sites^[27]
	Ethinyl estradiol		0.035 mg
	Norethindrone		0.4 mg
	Ethinyl estradiol		0.035 mg	13 cycles	Lumbar spine and femoral neck	No significant change BMD in any sites^[28]
	Norgestimate		0.180–0.250 mg	13 cycles	Lumbar spine and femoral neck	No significant change BMD in any sites^[28]

Androgen therapy

Recent studies have shown that androgen therapy in the dose of 50, 100, or 200 mg of micronized DHEA daily may increase bone mineral density (BMD), and prevent osteoporotic fracture. However, there is no established long term study to prove this effect.^[26]

Recombinant insulin like growth factor 1 (IGF-1)

Recombinant insulin like growth factor 1 (IGF-1) (30 μg/kg−1 twice per day) along with OCP (0.035 mg ethinyl estradiol and 0.4 mg norethindrone) prevents fracture in hypothalamic amenorrhea (due to anorexia nervosa) by increasing bone mineral density (BMD).^[27]

Recombinant leptin

Recent studies have shown that administering recombinant leptin (0.08 mg/kg) subcutaneous daily for 2–3 months can lead to an increase in bone formation markers; and also decrease fracture risk through secondary prevention.^[29]

Bisphosphonates

In adolescent women with anorexia-induced amenorrhea, alendronate (10 mg) with calcium (1200 mg) and vitamin D (400 IU) for a year has been associated with significant improvement in bone loss. Therefore, bisphosphonates can be used as secondary prevention.^[30]
Doses of bisphosphonates for secondary prevention of functional amenorrhea are as follows:

Medicine	Dose	Treatment duration	Bone mineral density (BMD) site	Outcome
Etidronate	200 mg daily	3 months	Tibial midshaft	Non-significant increase in BMD in all sites^[31]
Calcium	600 mg daily
Vitamin D	1 μg daily
Risedronate	5 mg	9 months	Lumbar spine and femoral neck	Increase BMD in lumbar spine not in femoral neck^[32]
Calcium	1500 mg
Vitamin D	400 IU
Alendronate	10 mg	12 months	Lumbar spine and femoral neck	Non-significant increase in BMD in all sites^[30]
Calcium	1200 mg
Vitamin D	400 IU

References

↑ Ortiz LD, Syro LV, Scheithauer BW, Rotondo F, Uribe H, Fadul CE; et al. (2012). "Temozolomide in aggressive pituitary adenomas and carcinomas". Clinics (Sao Paulo). 67 Suppl 1: 119–23. PMC 3328813. PMID 22584716.
↑ "Committee Opinion No. 698: Hormone Therapy in Primary Ovarian Insufficiency". Obstet Gynecol. 129 (5): e134–e141. 2017. doi:10.1097/AOG.0000000000002044. PMID 28426619.
↑ Bondy, Carolyn A. (2007). "Care of Girls and Women with Turner Syndrome: A Guideline of the Turner Syndrome Study Group". The Journal of Clinical Endocrinology & Metabolism. 92 (1): 10–25. doi:10.1210/jc.2006-1374. ISSN 0021-972X.
↑ Dickey RP, Taylor SN, Curole DN, Rye PH, Pyrzak R (1996). "Incidence of spontaneous abortion in clomiphene pregnancies". Hum. Reprod. 11 (12): 2623–8. PMID 9021363.
↑ Harborne L, Fleming R, Lyall H, Norman J, Sattar N (2003). "Descriptive review of the evidence for the use of metformin in polycystic ovary syndrome". Lancet. 361 (9372): 1894–901. doi:10.1016/S0140-6736(03)13493-9. PMID 12788588.
↑ Balasch J, Fábregues F, Creus M, Casamitjana R, Puerto B, Vanrell JA (2000). "Recombinant human follicle-stimulating hormone for ovulation induction in polycystic ovary syndrome: a prospective, randomized trial of two starting doses in a chronic low-dose step-up protocol". J. Assist. Reprod. Genet. 17 (10): 561–5. PMC 3455454. PMID 11209536.
↑ Steiner AZ, Terplan M, Paulson RJ (2005). "Comparison of tamoxifen and clomiphene citrate for ovulation induction: a meta-analysis". Hum. Reprod. 20 (6): 1511–5. doi:10.1093/humrep/deh840. PMID 15845599.
↑ Sabuncu T, Harma M, Harma M, Nazligul Y, Kilic F (2003). "Sibutramine has a positive effect on clinical and metabolic parameters in obese patients with polycystic ovary syndrome". Fertil. Steril. 80 (5): 1199–204. PMID 14607575.
↑ Jayagopal V, Kilpatrick ES, Holding S, Jennings PE, Atkin SL (2005). "Orlistat is as beneficial as metformin in the treatment of polycystic ovarian syndrome". J. Clin. Endocrinol. Metab. 90 (2): 729–33. doi:10.1210/jc.2004-0176. PMID 15536162.
↑ Azziz R, Ehrmann D, Legro RS, Whitcomb RW, Hanley R, Fereshetian AG, O'Keefe M, Ghazzi MN (2001). "Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial". J. Clin. Endocrinol. Metab. 86 (4): 1626–32. doi:10.1210/jcem.86.4.7375. PMID 11297595.
↑ Wang CF, Gemzell C (1980). "The use of human gonadotropins for the induction of ovulation in women with polycystic ovarian disease". Fertil. Steril. 33 (5): 479–86. PMID 6768596.
↑ Glueck, C.J; Wang, Ping; Fontaine, Robert; Tracy, Trent; Sieve-Smith, Luann (2001). "Metformin to restore normal menses in oligo-amenorrheic teenage girls with polycystic ovary syndrome (PCOS)11The full text of this article is available via JAH Online". Journal of Adolescent Health. 29 (3): 160–169. doi:10.1016/S1054-139X(01)00202-6. ISSN 1054-139X.
↑ Vescovi JD, Jamal SA, De Souza MJ (2008). "Strategies to reverse bone loss in women with functional hypothalamic amenorrhea: a systematic review of the literature". Osteoporos Int. 19 (4): 465–78. doi:10.1007/s00198-007-0518-6. PMID 18180975.
↑ Hergenroeder AC, Smith EO, Shypailo R, Jones LA, Klish WJ, Ellis K (1997). "Bone mineral changes in young women with hypothalamic amenorrhea treated with oral contraceptives, medroxyprogesterone, or placebo over 12 months". Am. J. Obstet. Gynecol. 176 (5): 1017–25. PMID 9166162.
↑ Castelo-Branco C, Vicente JJ, Pons F, Martínez de Osaba MJ, Casals E, Vanrell JA (2001). "Bone mineral density in young, hypothalamic oligoamenorrheic women treated with oral contraceptives". J Reprod Med. 46 (10): 875–9. PMID 11725730.
↑ Rickenlund A, Carlström K, Ekblom B, Brismar TB, Von Schoultz B, Hirschberg AL (2004). "Effects of oral contraceptives on body composition and physical performance in female athletes". J. Clin. Endocrinol. Metab. 89 (9): 4364–70. doi:10.1210/jc.2003-031334. PMID 15328063.
↑ De Crée C, Lewin R, Ostyn M (1988). "Suitability of cyproterone acetate in the treatment of osteoporosis associated with athletic amenorrhea". Int J Sports Med. 9 (3): 187–92. PMID 2970444.
↑ Cumming DC (1996). "Exercise-associated amenorrhea, low bone density, and estrogen replacement therapy". Arch. Intern. Med. 156 (19): 2193–5. PMID 8885817.
↑ Gibson JH, Mitchell A, Reeve J, Harries MG (1999). "Treatment of reduced bone mineral density in athletic amenorrhea: a pilot study". Osteoporos Int. 10 (4): 284–9. doi:10.1007/s001980050228. PMID 10692976.
↑ Warren MP, Brooks-Gunn J, Fox RP, Holderness CC, Hyle EP, Hamilton WG, Hamilton L (2003). "Persistent osteopenia in ballet dancers with amenorrhea and delayed menarche despite hormone therapy: a longitudinal study". Fertil. Steril. 80 (2): 398–404. PMID 12909505.
↑ Warren MP, Miller KK, Olson WH, Grinspoon SK, Friedman AJ (2005). "Effects of an oral contraceptive (norgestimate/ethinyl estradiol) on bone mineral density in women with hypothalamic amenorrhea and osteopenia: an open-label extension of a double-blind, placebo-controlled study". Contraception. 72 (3): 206–11. doi:10.1016/j.contraception.2005.03.007. PMID 16102557.
↑ Golden NH, Lanzkowsky L, Schebendach J, Palestro CJ, Jacobson MS, Shenker IR (2002). "The effect of estrogen-progestin treatment on bone mineral density in anorexia nervosa". J Pediatr Adolesc Gynecol. 15 (3): 135–43. PMID 12106749.
↑ Muñoz MT, Morandé G, García-Centenera JA, Hervás F, Pozo J, Argente J (2002). "The effects of estrogen administration on bone mineral density in adolescents with anorexia nervosa". Eur. J. Endocrinol. 146 (1): 45–50. PMID 11751066.
↑ Klibanski A, Biller BM, Schoenfeld DA, Herzog DB, Saxe VC (1995). "The effects of estrogen administration on trabecular bone loss in young women with anorexia nervosa". J. Clin. Endocrinol. Metab. 80 (3): 898–904. doi:10.1210/jcem.80.3.7883849. PMID 7883849.
↑ Karlsson MK, Weigall SJ, Duan Y, Seeman E (2000). "Bone size and volumetric density in women with anorexia nervosa receiving estrogen replacement therapy and in women recovered from anorexia nervosa". J. Clin. Endocrinol. Metab. 85 (9): 3177–82. doi:10.1210/jcem.85.9.6796. PMID 10999805.
↑ ^26.0 ^26.1 Gordon CM, Grace E, Emans SJ, Feldman HA, Goodman E, Becker KA, Rosen CJ, Gundberg CM, LeBoff MS (2002). "Effects of oral dehydroepiandrosterone on bone density in young women with anorexia nervosa: a randomized trial". J. Clin. Endocrinol. Metab. 87 (11): 4935–41. doi:10.1210/jc.2002-020545. PMID 12414853.
↑ ^27.0 ^27.1 Grinspoon S, Thomas L, Miller K, Herzog D, Klibanski A (2002). "Effects of recombinant human IGF-I and oral contraceptive administration on bone density in anorexia nervosa". J. Clin. Endocrinol. Metab. 87 (6): 2883–91. doi:10.1210/jcem.87.6.8574. PMID 12050268.
↑ Strokosch GR, Friedman AJ, Wu SC, Kamin M (2006). "Effects of an oral contraceptive (norgestimate/ethinyl estradiol) on bone mineral density in adolescent females with anorexia nervosa: a double-blind, placebo-controlled study". J Adolesc Health. 39 (6): 819–27. doi:10.1016/j.jadohealth.2006.09.010. PMID 17116511.
↑ Welt CK, Chan JL, Bullen J, Murphy R, Smith P, DePaoli AM, Karalis A, Mantzoros CS (2004). "Recombinant human leptin in women with hypothalamic amenorrhea". N. Engl. J. Med. 351 (10): 987–97. doi:10.1056/NEJMoa040388. PMID 15342807.
↑ ^30.0 ^30.1 Golden NH, Iglesias EA, Jacobson MS, Carey D, Meyer W, Schebendach J, Hertz S, Shenker IR (2005). "Alendronate for the treatment of osteopenia in anorexia nervosa: a randomized, double-blind, placebo-controlled trial". J. Clin. Endocrinol. Metab. 90 (6): 3179–85. doi:10.1210/jc.2004-1659. PMID 15784715.
↑ Nakahara T, Nagai N, Tanaka M, Muranaga T, Kojima S, Nozoe S, Naruo T (2006). "The effects of bone therapy on tibial bone loss in young women with anorexia nervosa". Int J Eat Disord. 39 (1): 20–6. doi:10.1002/eat.20197. PMID 16231362.
↑ Miller KK, Grieco KA, Mulder J, Grinspoon S, Mickley D, Yehezkel R, Herzog DB, Klibanski A (2004). "Effects of risedronate on bone density in anorexia nervosa". J. Clin. Endocrinol. Metab. 89 (8): 3903–6. doi:10.1210/jc.2003-031885. PMID 15292325.

Template:WH Template:WS

[pmid22584716-1] Ortiz LD, Syro LV, Scheithauer BW, Rotondo F, Uribe H, Fadul CE; et al. (2012). "Temozolomide in aggressive pituitary adenomas and carcinomas". Clinics (Sao Paulo). 67 Suppl 1: 119–23. PMC 3328813. PMID 22584716.

[pmid28426619-2] "Committee Opinion No. 698: Hormone Therapy in Primary Ovarian Insufficiency". Obstet Gynecol. 129 (5): e134–e141. 2017. doi:10.1097/AOG.0000000000002044. PMID 28426619.

[Bondy2007-3] Bondy, Carolyn A. (2007). "Care of Girls and Women with Turner Syndrome: A Guideline of the Turner Syndrome Study Group". The Journal of Clinical Endocrinology & Metabolism. 92 (1): 10–25. doi:10.1210/jc.2006-1374. ISSN 0021-972X.

[pmid9021363-4] Dickey RP, Taylor SN, Curole DN, Rye PH, Pyrzak R (1996). "Incidence of spontaneous abortion in clomiphene pregnancies". Hum. Reprod. 11 (12): 2623–8. PMID 9021363.

[pmid12788588-5] Harborne L, Fleming R, Lyall H, Norman J, Sattar N (2003). "Descriptive review of the evidence for the use of metformin in polycystic ovary syndrome". Lancet. 361 (9372): 1894–901. doi:10.1016/S0140-6736(03)13493-9. PMID 12788588.

[pmid11209536-6] Balasch J, Fábregues F, Creus M, Casamitjana R, Puerto B, Vanrell JA (2000). "Recombinant human follicle-stimulating hormone for ovulation induction in polycystic ovary syndrome: a prospective, randomized trial of two starting doses in a chronic low-dose step-up protocol". J. Assist. Reprod. Genet. 17 (10): 561–5. PMC 3455454. PMID 11209536.

[pmid15845599-7] Steiner AZ, Terplan M, Paulson RJ (2005). "Comparison of tamoxifen and clomiphene citrate for ovulation induction: a meta-analysis". Hum. Reprod. 20 (6): 1511–5. doi:10.1093/humrep/deh840. PMID 15845599.

[pmid14607575-8] Sabuncu T, Harma M, Harma M, Nazligul Y, Kilic F (2003). "Sibutramine has a positive effect on clinical and metabolic parameters in obese patients with polycystic ovary syndrome". Fertil. Steril. 80 (5): 1199–204. PMID 14607575.

[pmid15536162-9] Jayagopal V, Kilpatrick ES, Holding S, Jennings PE, Atkin SL (2005). "Orlistat is as beneficial as metformin in the treatment of polycystic ovarian syndrome". J. Clin. Endocrinol. Metab. 90 (2): 729–33. doi:10.1210/jc.2004-0176. PMID 15536162.

[pmid11297595-10] Azziz R, Ehrmann D, Legro RS, Whitcomb RW, Hanley R, Fereshetian AG, O'Keefe M, Ghazzi MN (2001). "Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial". J. Clin. Endocrinol. Metab. 86 (4): 1626–32. doi:10.1210/jcem.86.4.7375. PMID 11297595.

[pmid6768596-11] Wang CF, Gemzell C (1980). "The use of human gonadotropins for the induction of ovulation in women with polycystic ovarian disease". Fertil. Steril. 33 (5): 479–86. PMID 6768596.

[GlueckWang2001-12] Glueck, C.J; Wang, Ping; Fontaine, Robert; Tracy, Trent; Sieve-Smith, Luann (2001). "Metformin to restore normal menses in oligo-amenorrheic teenage girls with polycystic ovary syndrome (PCOS)11The full text of this article is available via JAH Online". Journal of Adolescent Health. 29 (3): 160–169. doi:10.1016/S1054-139X(01)00202-6. ISSN 1054-139X.

[pmid18180975-13] Vescovi JD, Jamal SA, De Souza MJ (2008). "Strategies to reverse bone loss in women with functional hypothalamic amenorrhea: a systematic review of the literature". Osteoporos Int. 19 (4): 465–78. doi:10.1007/s00198-007-0518-6. PMID 18180975.

[pmid9166162-14] Hergenroeder AC, Smith EO, Shypailo R, Jones LA, Klish WJ, Ellis K (1997). "Bone mineral changes in young women with hypothalamic amenorrhea treated with oral contraceptives, medroxyprogesterone, or placebo over 12 months". Am. J. Obstet. Gynecol. 176 (5): 1017–25. PMID 9166162.

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