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Leader in digital CPD for Southern African healthcare professionals use in gynaecology Introduction This expert review on the use and benefits of progesterone therapy in clinical gynaecological medicine provides clarity on the use of micronised progesterone in menopausal (MHT) and loss. It provides an up-to-date expert assessment of the available in South Africa with guidance on their use in luteal phase deficiency, prevention of miscarriage or preterm birth, and in the treatment of menstrual abnormalities.

KEY MESSAGES Dr Tobie de Villiers MB ChB, MMed (O&G), • Natural progesterone differs from the later development of so-called progestins which are synthetic derivatives FCOG (SA), FRCOG. of progesterone Consultant Gynaecologist • The development of synthetic progestins was accelerated by the findings of the Womens Health Initiative which Stellenbosch University highlighted the fact that unopposed oestrogen in MHT leads to endometrial hyperplasia and cancer and Panorama MediClinic, • In MHT, the beneficial breast cancer-reducing effect of oestrogen therapy alone is lost when combined with a Parow metabolically active progestin, such as acetate. However, when combined with progesterone, [email protected] the increased risk of breast cancer and increased risk of venous thrombotic events (VTEs) is attenuated • Route of administration is important to reducing side effects • Supplementation of progesterone by oral or vaginal route is very effective for the normalisation of cycle length and the amount of menstrual bleeding.

Progesterone is produced by the ovarian corpus both oestrogen and progesterone, with the luteum after ovulation in a normal menstrual resultant orderly shedding of the endometrium cycle. Progesterone transforms proliferative called menstruation. Absence of or deficiencies endometrium (oestrogen effect) into secretory in progesterone secretion in a cycle may lead endometrium. This prepares the endometrium to various gynaecological disorders that could for pregnancy implantation (Figure 1). Failure benefit from progesterone therapy. of pregnancy will lead to the withdrawal of

ENDOMETRIAL CHANGES Menstruation Menstruation

Day 1 Proliferation 12 Secretion Regression 28 OVARIAN HORMONES

Oestrogen Progesterone

Day 1 12 28 VASCULAR CHANGES

This report was made possible by an unrestricted educational grant from Cipla. The content of the report is independent of the sponsor. Day 1 12 28 Figure 1. The menstrual cycle Amended from the Women’s Health Journal Online, April 2017.

OCTOBER 2019 I 1 Progesterone use in gynaecology

Brief historical perspective1 Different groups described the isolation and formulation of the corpus luteum hormone in 1931-1934. The name progesterone was coined in 1934 after the conversion of pregnanediol to progesterone was discovered. The synthesis of progesterone from cholesterol was described in 1939, followed in 1941 by the synthesis of progesterone from (obtained from the bark of the Mexican yam tree) (Figure 2). Progesterone was initially restricted to intra- muscular administration, but the micronised Figure 2. The Mexican yam tree Source: Lehmann PA, Bolivar F, Quintero R. Russel E. Marker: form thereof, which has been available since Pioneer of the Mexican industry. J Chemical Education 1980, enables oral administration. 1973; 50: 195-199.

The Clinicians currently have available a group of Many progestogens have cross-reactivity with steroidal hormones with progestogenic action, receptors other than just the progesterone collectively called the progestogens. This receptor, meaning they may have agonist and/ group includes the natural , pro- or antagonist effects on oestrogen, , gesterone; the called dydro- glucocorticoid and mineralocorticoid recep- gesterone; several progesterone derivatives, tors. This could lead to unwanted side effects.3 including 17-hydroxyprogesterone derivatives The development of the synthetic proges- and 19-nortestosterone derivatives; as well as tins were accelerated by the discovery that a derivative.2 unopposed (oestrogen only) menopausal hor- All but natural progesterone are regarded mone therapy (MHT) leads to endometrial “All but natural as synthetic drugs and are known as proges- hyperplasia and cancer and that prevention tins. Some of the synthetic progestins must is possible with the concomitant use of a pro- progesterone be metabolised before they can exert their gestogen. Progestogens are currently used in a are regarded as biological function. Although all the pro- variety of applications such as oral contracep- synthetic drugs gesterones exert effects on the progesterone tives, MHT and the treatment of endometrio- receptors, they differ not only in respect of sis. This review will focus on the use of natural and are known as their potency but also their hormonal profile. progesterone in clinical practice. progestins.“

Progesterone Retroprogesterone Progesterone

Progesterone derivatives 17-OH-progesterone 19-progesterone 19-progesterone derivates derivates derivates Gonanes Pregnane Nor-Pregnane • • • Hydroxyprogesterone • Nomegestrole acetate • • caproate • • • • Hydroxyprogesterone • • • heptanoate • Nestorone • Ethinodiol diacetate • • Trimegeston • • • EARN FREE acetate • derivative CPD POINTS • Medroxyprogesterone acetate Join our CPD community at • acetate www.denovomedica.com Figure 3. Classification of progesterones

and start to earn today! Available forms of progesterone Progesterone is available in South Africa as: progesterone) indicated for luteal phase 1. Micronised oral tablets (100mg) indicated support in infertility treatment (Cyclogest®) for use in MHT (Utrogestan®) 3. Vaginal gel 8% (90mg per application) indi- 2. Vaginal pessaries (200mg micronised cated for luteal phase support (Crinone®). 2 I OCTOBER 2019 Progesterone use in gynaecology

Route of administation The local application of vaginal progester- breast exposure to progesterone as well as a one allows optimal delivery to the uterus with better side effect profile. In some countries, minimal doses and avoids the large number vaginal pessaries are also allowed to be applied of progesterone metabolites seen after oral rectally. It should be noted that progesterone administration because of the first-pass liver is poorly absorbed by the skin and the vaginal effect.4 Vaginal application allows for minimal gel should not be used transdermally. Clinical indications Menopausal hormone therapy (MHT) In the aftermath of the Women’s Health registered for MHT. Some concern, though, Initiative study, several principles were for- has been expressed that the endometrial sup- mulated to make MHT as safe as possible.5 pressive effect of systemic progesterone is The use of oestrogen alone lowers the risk less than that of the progestins.7 In 2016, an of breast cancer. This beneficial effect is lost expert panel of gynaecological endocrino- when oestrogen is opposed by a metabolically logists concluded that, when combined with active progestin such as medroxyprogester- oestrogens, oral MP provides endometrial one acetate. The increased risk of breast can- protection if applied sequentially for 12-14 cer and increased risk of venous thrombotic days/month at 200mg/day for up to five years. events (VTEs) associated with progestins Vaginal MP may provide endometrial protec- can be attenuated by combining oestrogen tion if applied sequentially for at least 10 days/ with natural progesterone.6 In South Africa, month at 4% (45mg/day) or every other day oral micronised progesterone (MP) 100mg at 100mg/day for up to 3-5 years.8 Long-term daily (continuous therapy) or 200mg daily safety and compliance have not been studied. for 10 days per month (sequential therapy) is

Progesterone and pregnancy loss Appropriate levels of progesterone after ovula- pregnancy may lead to unique clinical presen- tion are important for successful implantation tations of failed pregnancy. These will be dis- and continuation of pregnancy. Inappropriate cussed below. low levels of progesterone at various stages of

Luteal phase deficiency Luteal phase deficiency in natural cycles has (OR 1.77, CI 1.09-2.86) in the progesterone been recognised for many years. The advent group.9 Although some of the early pregnancy of ovulation induction, especially associated losses in IVF must be because of genetically with in vitro fertilisation (IVF) has highlighted abnormal embryos, a significant proportion is this condition. In IVF, progesterone produc- secondary to endometrial conditions. Routine tion is decreased secondary to supraphysi- progesterone support in IVF is the norm in ological levels of oestrogen as well as reduced most IVF units in South Africa, and vaginal granulosa cells secondary to ova harvesting. MP pessaries are registered for this purpose. A recent Cochrane meta-analysis comparing Their use may be started directly after ova progesterone support in IVF to placebo or harvesting or after positive pregnancy test. no treatment, showed a higher live-born rate

Prevention of miscarriage Progestogens have controversially been used levels cannot be made accurately as progester- off-label for the prevention of miscarriage one is secreted in a pulsatile way. Low proges- for many years. This practice is based on the terone levels may be the result of miscarriage knowledge that surgical lobectomy or the and not the cause. A recent large randomised chemical inhibition of progesterone receptors controlled trial in patients diagnosed with () before seven weeks causes mis- recurrent miscarriage failed to show benefit in carriage. The diagnosis of low progesterone patients treated with vaginal MP.10

Threatened miscarriage Bleeding in the first 20 weeks of pregnancy MP after early pregnancy bleeding to prevent with a closed cervix is associated with an miscarriage is controversial, but it is still often increased risk of miscarriage although this used off-label. There is no evidence to support may occur in 25% of . Vaginal the use of vaginal MP for this indication. OCTOBER 2019 I 3 Progesterone use in gynaecology

Prevention of preterm birth Although no progesterone is indicated for a recent 2016 meta-analysis favoured the use this purpose in South Africa, the off-label of vaginal MP for the prevention of preterm use of vaginal MP for the prevention of pre- delivery before 34 weeks.11 The meta-analysis term birth before 34 weeks in patients with a included one large trial that failed to show prior history of preterm delivery, or a short benefit in vaginal MP-treated women. The cervix in their current pregnancy, is incorpo- use of vaginal MP for the prevention of rated in the management guidelines of most preterm birth in twin pregnancies remains South African academic institutions. Various controversial. trials have been inconsistent in outcomes but

Treatment of menstrual abnormalities Anovulatory cycles may lead to irregular cycles by the oral or vaginal route from day 14-21 and menorrhagia. This is often the case in the of the cycle is very effective for normalisa- perimenopause where anovulation is com- tion of cycle length and amount of menstrual mon. The supplementation of progesterone bleeding.

Side effects of progesterone therapy The most common side effect of progesto- of progestogen intolerance is smaller when gen therapy is sleepiness, which can be an MP is used compared to other progestins. The advantage if it is taken at night. Intolerance risk is also smaller when the vaginal route of of progestogen therapy may be a major cause application is used compared to the oral route, of non-compliance in hormonally vulnerable as the uterine first pass effect allows smaller EARN FREE women. Women may report premenstrual but effective dosages while serum levels remain CPD POINTS symptoms, anxiety and depression. The risk low.

Are you a member of Safety aspects Southern Africa’s leading It has been discussed that some progestins may 34th week of pregnancy. Progestins derived digital Continuing attenuate the beneficial effect of oestrogen on from 19-nortestosterone have been associ- Professional Development breast cancer and cardiovascular disease and ated with the virilisation of female offspring increase the risk of VTEs. This is not the case in rats and should be avoided in humans. The website earning FREE CPD if MP is used either orally or vaginally. MP is progestin dydrogesterone could not be linked points with access a natural hormone of pregnancy and no side to birth defects in over 10 million human foe- to best practice content? effects during pregnancy have been described. tuses exposed to it. It can thus safely be used from ovulation to the Only a few clicks and you can register to start earning today Summary The progestogens are a group of steroidal hor- administered orally or vaginally, is registered Visit mones that interact with cellular progesterone in South Africa for use in MHT and luteal receptors. The progestogens have a wide appli- phase support. Off-label use of vaginal MP is www.denovomedica.com cation in clinical medicine. The progestins common for the prevention of preterm birth are widely used in contraception and medi- before 34 weeks in patients with a prior his- For all Southern African cal therapy for endometriosis. MP, whether tory of preterm delivery or a short cervix. healthcare professionals References Click on reference to access the scientific article 1. Piette P. The history of natural progesterone, the never-ending 7. Davey DA. Menopausal hormone therapy: a better and safer story. Climacteric 2018; 21(4): 308-314. future. Climacteric 2018; 21(5): 454-461. 2. Schindler AE, Campagnoli C, Druckmann R, et al. 8. Stute P, Neulen J, Wildt L. The impact of micronized Classification and pharmacology of progestins. Maturitas progesterone on the endometrium: a systematic review. 2003; 46 (Suppl. 1): S7-S16. Climacteric 2016; 19(4): 316-328. 3. Schindler AE, Campagnoli C, Druckmann R, et al. 9. Carp HJA. Progestogens and pregnancy loss. Climacteric Classification and pharmacology of progestins (Reprint). 2018; 21(4): 380-384. Maturitas 2008; 61(1-2): 171-180. 10. Coomarasamy A, Williams H, Truchanowicz E, et al. A Find us at 4. Warren MP. Vaginal progesterone and the vaginal first-pass randomized controlled trial of progesterone in women with effect. Climacteric 2018; 21(4): 355-377. recurrent miscarriages. N Engl J Med 2015; 373(2): 2141-2148. 5. De Villiers TJ, Hall JE, Pinkerton JV, et al. Revised global 11. Romero R, Nicolaides KH, Conde-Agudelo A, et al. Vaginal DeNovo Medica consensus on menopausal hormone therapy. Climacteric progesterone decreases preterm birth < 34 weeks gestation 2016; 19(4): 313-315. in women with a singleton pregnancy and short cervix: an 6. Baber R, Panay N, Fenton A, et al. 2016 IMS update meta-analysis including data from the OPPTIMUM @deNovoMedica Recommendations on women’s midlife health and menopause study. Ultrasound Obstet Gynecol 2016; 48(3): 308-317. hormone therapy. Climacteric 2016; 19(2): 109-150.

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